AU2022230013B2

AU2022230013B2 - New-type benzazepine fused ring derivative

Info

Publication number: AU2022230013B2
Application number: AU2022230013A
Authority: AU
Inventors: Hongfu LU; Jianbiao PENG; Dezhi QIU
Original assignee: Jiangxi Jemincare Group Co Ltd; Shanghai Jemincare Pharmaceuticals Co Ltd
Current assignee: Jiangxi Jemincare Group Co Ltd; Shanghai Jemincare Pharmaceuticals Co Ltd
Priority date: 2021-03-05
Filing date: 2022-03-04
Publication date: 2025-01-23
Anticipated expiration: 2042-03-04
Also published as: BR112023017755A2; EP4302762A1; IL305652A; JP7607788B2; AU2022230013A1; TW202246273A; EP4302762A4; KR20230152111A; US20240190884A1; US12600729B2; CN115427048A; JP2024509437A; WO2022184172A1; CA3210848A1

Abstract

A benzazepine fused ring derivative as represented by formula (I) or a pharmaceutically acceptable salt thereof, and the use of a compound in the diagnosis, prevention and/or treatment of diseases related to vasopressin receptors.

Description

NEW-TYPE BENZAZEPINE FUSED RING DERIVATIVE

[0001] The present invention claims the right of the following priorities: CN202110264947.3, application date: March 5, 2021;

CN202110559685.3, application date: May 21, 2021;

CN202210198716.1, application date: March 2, 2022.

TECHNICAL FIELD

[0002] The present disclosure relates to a new-type benzazepine fused ring derivative and a

salt thereof. The present disclosure also relates to a use of a medicament comprising the

benzazepine fused ring derivative and the salt thereof as active ingredients in the diagnosis,

prevention, and/or treatment of diseases related to vasopressin receptors.

BACKGROUND

[0003] Hormones play an important role in the regulation of homeostasis in the human body, among which arginine vasopressin (AVP) is closely related to the regulation of water and

sodium metabolism in the human body. Metabolic disturbances of arginine vasopressin (AVP)

can cause diseases such as hyponatremia, syndrome of inappropriate antidiuretic hormone

secretion, congestive heart failure, liver cirrhosis, kidney disease, hypertension, and edema.

Arginine vasopressin (AVP) receptor antagonists can inhibit the combination of AVP and

receptors, thereby playing a therapeutic role in the above diseases. The arginine vasopressin

V2 receptor antagonist represented by Tolvaptan can increase the excretion of free water

without affecting the metabolism of electrolytes, thus becoming an ideal drug for the treatment

of the above diseases. However, the marketed AVP V2 receptor antagonists, such as

Tolvaptan, are metabolized by liver metabolic enzymes, which produce a large number of

metabolites in the body and cause severe drug-induced liver toxicity. The FDA issued a black

box warning on the drug's product label, limiting its application. Therefore, developing a

new-type V2 receptor antagonist with high efficiency and low side effects is very important.

CONTENT OF THE PRESENT INVENTION

[0001] Herein disclosed is a compound of formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, A

(R 2 A i RI)

N T, O

0 N H

[0002] wherein

[0003] ring A is selected from 4- to 6-membered heterocyclyl and C3 .6 cycloalkyl, and the 4- to 6-membered heterocyclyl or C 3 -6 cycloalkyl is optionally substituted by 1, 2, or 3 RA;

[0004] ring B is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R3 ;

[0005] ring C is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4 ;

[0006] T 1, T 2 are each independently selected from N and C(RT);

[0007] R1, R2, R3, RA, RT are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2

, C 1 .6 alkyl, and C1.6 heteroalkyl, and the C 1 .6 alkyl or C 1-6heteroalkyl is optionally substituted by 1, 2, or 3 R;

[0008] each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C1-6 alkoxy, C 1 -6 alkylamino, C 3 -6 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the C 1 .6 alkyl, C1-6 alkoxy, C 1 -6 alkylamino, C 3 -6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R 4a;

[0009] R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, Ci 6 alkoxy, and C 1 .6 alkylamino, and the C 1 .6 alkyl, C 1 .6 alkoxy, and C 1-6 alkylamino are optionally substituted by 1, 2, or 3 R';

[0010] R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , and C 1 -6 alkyl;

[0011] ml, m2 are each independently selected from 0, 1, or 2;

[0012] and when ring A is selected from 4- to 6-membered heterocyclyl, the compound of

0

° YN 0 NH

a 0/ e I

0 N N formula (I) is not selected from H , H ,or

[0013] the 4- to 6-membered heterocyclyl, C 1-6 heteroalkyl, or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=0)2-, and N.

[0014] Also herein disclosed is a compound of formula (II), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

3x),

N T1 0

0 N H (11)

[0015] wherein X1, X 2 , X 3 are each independently selected from 0, C(RA)2, and NRA;

[0016] ring B is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R3 ;

[0017] ring C is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4 ;

[0018] T1, T2 are each independently selected from N and C(R);

[0019] RI, R2, R3, RA, RTare each independently selected from H, F, Cl, Br, I, CN, OH, NH 2

, CI-6 alkyl, and C1 -6heteroalkyl, and the C1 -6 alkyl or C1 -6heteroalkyl is optionally substituted by 1, 2, or 3 R;

[0020] each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1 -6 alkyl, CI-6 alkoxy, C 1-6 alkylamino, C 3 -6 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the C1 -6 alkyl, CI-6 alkoxy, CI-6 alkylamino, C 3 -6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R 4a;

[0021] R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, Ci 6 alkoxy, and C 1-6 alkylamino, and the C 1-6 alkyl, C 1-6 alkoxy, and C1-6 alkylamino are optionally substituted by 1, 2, or 3 R';

[0022] R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , and C1 -6 alkyl;

[0023] ml, m2, n are each independently selected from 0, 1, or 2;

[0024] and when X1, X 3 are selected from 0 at the same time, the compound of formula (II) is

0 o

N

0

not selected from ;

[0025] the CI-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=0) 2 -, and N.

[0026] Also herein disclosed is a compound of formula (11-1),(11-2),(11-3), or (11-4), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

1)O R2R N\T 1 N T1-T 0 N j T10T

0 N O N 0 N H H H (11-i) (11-2) (11-3)

(R2 R

H (11-4) wherein ring B, ringC, X 1, X 2 , X 3 , Ti, T2, RI, R2 , ml, m2, n are as defined above.

[0027] Also herein disclosed is a compound of formula (III), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

(2 (X)N T 3Rim

RR4 0 0 Y2,Y 1 N H

[0028] wherein X 1, X 2 , X 3 are each independently selected from 0, C(RA)2, and NRA;

[0029] T1, T2are each independently selected from N andC(R);

[0030] Y 1, Y2 are each independently selected from N and C(Ry);

[0031] R 1, R2, R3, RA, RT, Ry are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6alkyl, andC 1-6heteroalkyl, and the C1 -6alkyl orC1 -6heteroalkyl is optionally substituted by 1, 2, or 3 R;

[0032] each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1 -6 alkyl, CI-6 alkoxy,C 1-6 alkylamino,C 3-6cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and theC1 -6 alkyl, C1-6 alkoxy, C 1 -6 alkylamino, C 3 -6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4a;

[0033] R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6alkyl, Ci 6alkoxy, andC 1-6alkylamino, and theC 1-6alkyl, C1 -6alkoxy, andC1-6alkylamino are optionally substituted by 1, 2, or 3 R';

[0034] R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , andC1 -6alkyl;

[0035] ml, m2, m3, m4, n are each independently selected from 0, 1, or 2;

[0036] and when Xi,X 3 are selected from 0 at the same time, the compound of formula (III) is

o e 0

N 0

N H not selected from

[0037] the C1-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=0) 2 -, and N.

[0038] Also herein disclosed is a compound of formula (11I-1), (111-2),(111-3), or (111-4), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

o 2 R3R

N T1 3 N T1 )m

o 0 0 0 H R4 H ( R2 R2 R2RR1

2 R2R N/X2, Y, a , N T ) r heenX1 2,XT1 2

phracuiclly o 0 acepabe al-terof 0 YiR2, R1,R2,R,4ml, Y2 , 0 m2, m3,R m4 n rae idaoe 01 Y12 H~ H R 4) H4)

[0042] , R il wherein X1, X2, X3, T1, T2

, Y 1 , Y2 , R ,R; 3 ,R 4 ,ml,m2,m3,m4,nareasdefinedabove. 100391 Alsohereindisclosed is a compound of formulaTV), an opticalisomer thereof, ora pharmaceutically acceptable salt thereof, RA SN"

N ~T T1I 3

Y1 N H

(IV)

100401 whereinT1, T 2 are each independently selected from 0,N, andC(RT); 100411 Y 1 , Y2 are each independently selected from NandC(Ry); 100421 R1, R 2 , R 3 , RA, RT, Ry are each independently selected from H,F, Cl, Br,1, CN, OH, NH 2 , C 1-6 alkyl, and C 1 -6 heteroalkyl, and the C1 -6 alkyl or C 16 heteroalkyl is optionally substituted by 1,2, or 3R;

[0043] eachR 4 isindependently selected from H,F,Cl, Br, I, CN, OH, NH 2 , C 1 -6alkyl, C16 alkoxy, C 1-6 alkylamino, C3 6 cycloalkyl, phenyl, and 5-to 6-membered heteroaryl, and the C 1 6- alkyl, C1-6 alkoxy, C1-6 alkylamino, C3 -6 cycloalkyl, phenyl, or 5-to6-membered heteroaryl is optionally substituted by1,2, or 3R 4a,; 100441 R, R4 aare each independently selected from H, F,Cl, Br,1, CN, OH,NH42 , C1-6alkyl, Ci 6 alkoxy, and C 1-6 alkylamino, and the C 1-6 alkyl, C1-6 alkoxy, and C1-6 alkylamino are optionally substituted by 1, 2, or 3 R';

[0045] R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , and C1-6 alkyl;

[0046] m2, m3, n are each independently selected from 0, 1, or 2;

[0047] the CI-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=0) 2 -, and N.

[0047a] According to a first embodiment of the present invention there is provided a compound of formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

A

(R2PR

N T, 0

H

wherein ring A is selected from 4- to 5-membered heterocyclyl, and the 4- to 5-membered heterocyclyl is optionally substituted by 1, 2, or 3 RA; ring B is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6 membered heteroaryl is optionally substituted by 1, 2, or 3 R3 ; ring C is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6 membered heteroaryl is optionally substituted by 1, 2, or 3 R4 ; Ti, T2 are each independently selected from N and C(RT); R 1, R2 , R3, RA, RT are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1 -6 alkyl, and CI-6 heteroalkyl, and the C1 -6 alkyl or C1-6 heteroalkyl is optionally substituted by 1, 2, or 3 R; each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , CI-6 alkyl, C1-6 alkoxy, C 1-6 alkylamino, C 3 -6cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the CI-6 alkyl, Ci 6 alkoxy, C 1-6 alkylamino, C 3 -6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R 4 a; R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C1 - 6 alkoxy, and C1-6 alkylamino, and the C 1-6 alkyl, C1 -6 alkoxy, and CI-6 alkylamino are optionally substituted by 1, 2, or 3 R'; R'is selected from H, F, Cl, Br,I, CN, OH, NH 2 , and C1 -6 alkyl; ml, m2 are each independently selected from 0, 1, or 2; the 4- to 5-membered heterocyclyl comprises only 1 heteroatom or heteroatom group, and the heteroatom or heteroatom group is selected from -0-, -NH-, and N; the C1 -6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=)-, -C(=0)O-, -S(=0)-, S(=0) 2 -, and N.

[0047b]According to another embodiment of the present invention there is provided a compound of formula (III), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

(x3),n

R2R

T N T 1 fro Ra)

0 0

Y1 N H

wherein oneofXi, X 2 andX 3 is selected from 0and NRA,and theothersare C(RA)2; T 1 , T 2 are each independently selected from N and C(R); Y1 , Y2 are each independently selected from NandC(Ry); Ri, R2 ,R 3 ,RA,RT,Ry are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2

, C1-6alkyl, andC1 -6heteroalkyl, and theC1 -6alkyl orC1 -6heteroalkyl is optionally substituted by 1, 2, or 3 R; each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6alkyl,C1-6alkoxy, C 1-6alkylamino,C 3-6cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and theCI-6alkyl, Ci 6alkoxy,C 1 -6alkylamino,C 3-6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4 a; R, R4a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl,C1 -6 alkoxy, andC1-6alkylamino, and theC 1-6 alkyl, C 1-6 alkoxy, andC1-6alkylamino are optionally substituted by 1, 2, or 3 R'; R' is selected from H, F, Cl, Br,I, CN, OH, NH 2 , andC1 -6alkyl; ml, m2, m3, m4 are each independently selected from 0, 1, or 2; n is 0 or 1; theC1-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, S(=0) 2 -, and N.

[0047c]According to another embodiment of the present invention there is provided a compound of formula (IV), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, RA

n N (R 2 R,

N T1 R 2

Y1 N H (IV) wherein Ti, T2 are each independently selected from 0, N, andC(RT); Yi, Y2 are each independently selected from N and C(Ry); Ri, R2 , R3, RA, RT, Ry are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2

, C 1-6 alkyl, and C1 -6heteroalkyl, and the C1-6 alkyl or C1 -6heteroalkyl is optionally substituted by 1, 2, or 3 R; each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C1-6 alkoxy, CI-6 alkylamino, C 3 -6cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the CI-6 alkyl, C1 6 alkoxy, CI-6 alkylamino, C 3 -6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R 4a; R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C1 -6 alkoxy, and C 1-6 alkylamino, and the C 1-6 alkyl, C1 -6 alkoxy, and CI-6 alkylamino are optionally substituted by 1, 2, or 3 R'; R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , and C1 -6 alkyl; m2, m3 are each independently selected from 0, 1, or 2; n is 0 or 1; the C 1-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, S(=0) 2 -, and N.

[0048] According to another embodiment of the present invention there is provided a compound of formula (V-1), (V-2), (V-3), or (V-4), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

R1 ( RRA (

,R2 RRA Nn )nN N/

. R R (R 2 T, R R3 OR N R N T R1,

S o R4 s s f R 2,Y 2 , 1 2 Y1 N Y1 N 2 Y1 N HH H

(V-i) (V-2) (V-3)

RA

_N T1 3 )

0 0 R4 Y, N H

(V-4) ~ ,whereinI,1T2, YI,Y 2 , Ri,R 2 , R 3 , R 4 , RA, m2, m3, nare as defined above. 100491 In some embodiments of the present disclosure, the R 4 is selected from H, F,Cl, Br, ,

N N CN, OH, NH 2 , CH3 , CF3 ,'/, '0 ''O, H , I , cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thienyl, and thiazolyl, and other variables are as defined in the present disclosure.

[0050] According to certain disclosures, the ring A is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, cyclobutyl, cyclopentyl, or cyclohexyl is optionally substituted by 1 or 2 RA, and other variables are as defined in the present disclosure.

[0050a] In certain embodiments of compounds according to the present invention, ring A is selected from azetidinyl, oxetanyl, pyrrolidinyl, and tetrahydrofuranyl, and the azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl is optionally substituted by 1 or 2 RA.

~NH

[0051] In some embodiments of the present disclosure, the ring A is selected from H N- O O NH

, and '.,and other variables are as defined in the present disclosure.

[0052] In some embodiments of the present disclosure, the ring B is selected from phenyl and pyridyl, and the phenyl or pyridyl is optionally substituted by 1, 2, or 3 R3, and other variables are as defined in the present disclosure.

[0053] In some embodiments of the present disclosure, the ring B is selected from and

N '', and other variables are as defined in the present disclosure.

[0054] In some embodiments of the present disclosure, the ring C is selected from

FE F F Cl

,and , and other variables are as defined in the present disclosure.

[0055] According to another embodiment of the present invention there is provided a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from

C1 C\ CF C

NH NH 0~

N0FC0 N0 CFN N N N/ H NH H H OH 0 UI- ,9

[0055a1According to certain aspects of this embodiment the optical isomer is selected from:

C1 C1 CI ~C

N 0 FC N 0 F 3C N 0 F,0 N 0 F3C

o 0 N/ 0/ \NN \/ N

H N /'NH NH H1 a C C1 H" eN CI C N F3C N 0FC N -& 0 N0 I 0 -N 3 N H \/N and H~\/

100561 In yet another aspect of the present disclosure, the present disclosure also provides a compound of the following formula, an optical isomer thereof, or apharmaceutically acceptable salt thereof, selected from /-NH NH ciNH /-NH -lC CI - CC C

N N 0N 0 N 0

o \/ 0~ o/a\N~\N H H H H

/'HH NH

NCI 1 1 CI NNN N - N 3 F3CF NF 0 0 3C 3C o 0 0- N~ N,N~ NN \ N \

N- -N

\CI \C /C CI N N - r N -&

o0 ' 0 CF3 0 "- 0 CF3 0 1 "- 0 CF3 0 " 0 CF3 N N N~N N " N N NN 1- UI-

C, C1 CI

N 0N N N 0 H H HH

S0 ;7-9 CI C1 CI Ci

N N N 0N

o0 \ N N/ 0 d ,\ ~ \ -NH H H CI 1C C1

N QOI N 01 N c1 N oC1

NNN NN

*CI C1 CI CI

0,-&N N,& NN N-N 0N /N H HHH

[0057] According to another embodiment of the present invention there is provided a use of the compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vlb receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system.

[0057a] According to yet another embodiment of the present invention, there is provided a method for the prevention or treatment of diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vlb receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system, said method comprising administering to a patient in need a compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to the invention.

[0058] In some embodiments of the present disclosure, the diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vlb receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system comprise: hypertension, Reye's syndrome, dysmenorrhea, premature delivery, corticotropin-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone secretion, hyponatremia caused by chronic heart failure/liver cirrhosis/inappropriate antidiuretic hormone secretion, or polycystic kidney disease.

[0059] The present disclosure has at least one of the following technical effects:

10a

[0063] 1) Compared with the prior art (such as the positive drug Tolvaptan), the compounds of the present disclosure have lower liver toxicity, and the specific performance includes but

not limited to: the compounds of the present disclosure can reduce the inhibition of bile

excretion into the bile duct, do not capture GSH (glutathione) and/or do not produce DM4103

like metabolites;

[0064] 2) compared with the prior art, the proportional dose-effect of the compounds of the present disclosure has no hook effect in AVP-induced LLC-PK1 cell proliferation, so the

compounds of the present disclosure have a better curative effect;

[0065] 3) compared with the prior art (such as the positive drug Lixivaptan), the compounds

of the present disclosure do not inhibit CYP;

[0066] 4) compared with the prior art, the compounds of the present disclosure have a longer

half-life, thus prolonging the drug effect;

[0067] 5) compared with the prior art, the compounds of the present disclosure have high

selectivity for V2 receptor.

[0068] Definition and description

[0069] Unless otherwise specified, the following terms and phrases used herein are intended

to have the following meanings. A specific phrase or term should not be considered indefinite

or unclear in the absence of a particular definition but should be understood according to the

common meaning. When a trading name appears herein, it is intended to refer to its

corresponding commercial product or active ingredient thereof.

[0070] As used herein, the phrase "at least one" when referring to a list of one or more than

one element should be understood to mean at least one element selected from any one or more

elements in the list of elements, but not necessarily including at least one of each element

specified in the list of elements, and not excluding any combination of elements in the list of

elements. This definition also allows that elements may optionally be present other than the

elements specifically identified within the list of elements to which the phrase "at least one"

refers, whether related or unrelated to those elements specifically identified.

[0071] The term "pharmaceutically acceptable" is used herein in terms of those compounds,

materials, compositions, and/or dosage forms, which are suitable for use in contact with human

and animal tissues within the scope of reliable medical judgment, with no excessive toxicity, irritation, an allergic reaction, other problems, or complications, commensurate with a reasonable benefit/risk ratio.

[0072] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present disclosure that is prepared by reacting the compound having a specific substituent of

the present disclosure with a relatively non-toxic acid or base. When the compound of the

present disclosure contains a relatively acidic functional group, a base addition salt can be

obtained by bringing the neutral form of the compound into contact with a sufficient amount

of base in a pure solution or a suitable inert solvent. The pharmaceutically acceptable base

addition salt includes a salt of sodium, potassium, calcium, ammonium, organic amine,

magnesium, or similar salts. When the compound of the present disclosure contains a

relatively basic functional group, an acid addition salt can be obtained by bringing the neutral

form of the compound into contact with a sufficient amount of acid in a solution or a suitable

inert solvent. Examples of the pharmaceutically acceptable acid addition salt include an

inorganic acid salt, wherein the inorganic acid includes, for example, hydrochloric acid,

hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen

phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid; and an organic acid salt, wherein the organic acid includes, for example,

acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid,

benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid,

benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic

acid; and salts of amino acid (such as arginine), and a salt of an organic acid such as glucuronic

acid. Certain specific compounds of the present disclosure contain both basic and acidic

functional groups, thus can be converted to any base or acid addition salt.

[0073] The pharmaceutically acceptable salt of the present disclosure can be prepared from

the parent compound that contains an acidic or basic moiety by a conventional chemical

method. Generally, such salt can be prepared by reacting the free acid or base form of the

compound with a stoichiometric amount of an appropriate base or acid in water or an organic

solvent or a mixture thereof.

[0074] The compounds of the present disclosure may exist in specific geometric or

stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D) isomers, (L)-isomers, racemic mixtures, and other mixtures thereof, such as enantiomers or diastereomeric enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included within the scope of the present disclosure.

[0075] Unless otherwise specified, the absolute configuration of a stereogenic center is represented by a wedged solid bond (/) and a wedged dashed bond (/),and the relative configuration of a stereogenic center is represented by a straight solid bond (1 ) and a straight dashed bond( ). For example, the straight solid bond and the dashed bond at the Cl and /-NH

N

C2 atoms in H indicate that the two bonds linked to Cl and C2 are facing inward and outward, respectively, i.e., representing two trans-configuration compounds, NH /-NH ci ci N N

N/H or N and if the compound is in a cis structure, it can be represented by two straight solid bonds (/)or two straight dashed bonds (/),i.e., NH NH Ci CI

N F 3C N 0 F3 C

H and H , which both represent NH NH CI. - ci 0 N 3 N HF3 C N F3 C

o NN \ or 0 ~ ji \

[0076] The compounds of the present disclosure may exist in particular. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers possibly exist (such as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomer (also called prototropic tautomer) includes interconversion through proton migration, such as keto-enol isomerization and imine enamine isomerization. Valence tautomer includes some recombination of bonding electrons for mutual transformation. A specific example of keto-enol tautomerization is the tautomerism between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0077] The compound of the present disclosure may contain an unnatural proportion of atomic isotope at one or more than one atom that constitutes the compound. For example, the

compound can be labeled with a radioactive isotope, such as tritium (3H), iodine-125 (1251), or

C-14 (14 C). For another example, deuterated drugs can be formed by replacing hydrogen with

deuterium, the bond formed by deuterium and carbon is stronger than that of ordinary hydrogen

and carbon, compared with non-deuterated drugs, deuterated drugs have the advantages of

reduced toxic and side effects, increased drug stability, enhanced efficacy, extended biological

half-life of drugs, etc. All isotopic variations of the compound of the present disclosure,

whether radioactive or not, are encompassed within the scope of the present disclosure.

"Optional" or "optionally" means that the subsequent event or condition may occur but not

requisite, and the description includes the instance in which the event or condition occurs and

the instance in which the event or condition does not occur. ' N

[0078] When the valence bond of a group has a dashed line ", such as in" ", the dashed line indicates the linkage site of the group to the rest of the molecule. When there is

"- "on a single bond, for example, in the dashed line represents a single bond or absent,

and also means that "=='" represents a single bond "-"or a double bond "

[0079] The term "substituted" or "substituted by..." means one or more hydrogen atoms on a

specific atom are substituted by the substituent, including deuterium and hydrogen variables,

as long as the valence of the specific atom is normal and the substituted compound is stable.

The term "optionally substituted" or "optionally substituted by..." means an atom can be

substituted with a substituent or not, unless otherwise specified, the type and number of the

substituent may be arbitrary as long as being chemically achievable.

[0080] When any variable (such as R) occurs in the constitution or structure of the compound

more than once, the definition of the variable at each occurrence is independent. Thus, for example, if a group is substituted by 1, 2, or 3 R', the group can be optionally substituted by 1,

2, or 3 R', wherein the definition of R' at each occurrence is independent. Moreover, a

combination of the substituent and/or the variant thereof is allowed only when the combination

results in a stable compound.

[0081] When one of the variables is selected from a single bond, it means that the two groups 0

linked by the single bond are linked directly. For example, when Li in represents 0

a single bond, the structure is actually 2

[0082] When the listed substituents do not indicate via which atom it is linked to the

substituted group, this substituent can be bonded via any atom, for example, pyridyl, as a

substituent, can link to the substituted group via any carbon atom on the pyridine ring.

[0083] When the listed linking group does not indicate the direction for linking, the direction

for linking is arbitrary, for example, the linking group L contained in > is -CH 2 0-,

- 0

then -CH 20- can link phenyl and cyclopentyl to form in the direction same as

left-to-right reading order, and can link phenyl and cyclopentyl to form in the

direction contrary to left-to-right reading order. A combination of the linking groups,

substituents and/or variables thereof is allowed only when such combination can result in a

stable compound.

[0084] Unless otherwise specified, the number of atoms on a ring is usually defined as the

number of membered rings, such as a "3- to 6-membered ring" is a "ring" with 3 to 6 atoms

arranged around it.

[0085] Unless otherwise specified, the term "C 1-6 alkyl" refers to a linear or branched

saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl includes Ci-5

alkyl, C 1-4alkyl, C 1 -3alkyl, C 1-2 alkyl, C2-6 alkyl, C2-4 alkyl, C 6 alkyl, C 5 alkyl, etc.; it can be H monovalent (such as CH 3), divalent (-CH 2 -), ormultivalent (such as -' 's). ExamplesofCi

6 alkyl include, but are not limited to, CH3 , , , , , etc.

[0086] Unless otherwise specified, the term "Ci-4 alkyl" refers to a linear or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1 4 alkyl includes C 1-2

alkyl, C 1-3 alkyl, C34 alkyl, C2-3 alkyl, etc.; it can be monovalent (such as CH3 ), divalent( H CH2-), or multivalent (such as ). Examples of C1-4 alkenyl include, but are not limited

to, CH3, , u , ',, -.

[0087] Unless otherwise specified, "C2-3 alkenyl" refers to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond,

and the carbon-carbon double bond may be located at any position of the group. The C2-3

alkenyl includes C3 alkenyl and C2 alkenyl; it can be monovalent, divalent, or multivalent.

Examples of C 2 -3 alkenyl include, but are not limited to, ,'

[0088] Unless otherwise specified, "C2-3 alkynyl" refers to a linear or branched hydrocarbon

group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, and

the carbon-carbon triple bond may be located at any position of the group. It can be

monovalent, divalent, or multivalent. The C2-3 alkynyl includes C3 alkynyl and C2 alkynyl.

Examples of C2-3 alkynyl include, but are not limited to, , , -1 , '" .

[0089] The term "heteroalkyl" by itself or in combination with another term means a stable linear or branched alkyl group or a combination thereof consisting of a certain number of

carbon atoms, and at least one heteroatom or heteroatom group. In some embodiments, the

heteroatom is selected from B, 0, N, and S, wherein the nitrogen and sulfur atoms are

optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other

embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O),

S(=0) 2 -, -C(=0)N(H)-, -N(H)-, -C(=NH)-, -S(=0) 2 N(H)-, and -S(=O)N(H)-. In some

embodiments, the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C1 .

3 heteroalkyl. A heteroatom or heteroatom group may be located at any internal position

within a heteroalkyl, including the site where the alkyl group is linked to the rest of the molecule, but the term "alkoxy" is a conventional expression referring to those alkyl groups linked to the rest of the molecule through an oxygen atom. Examples of heteroalkyl include, but are not limited to, -OCH 3, -OCH 2CH3 , -OCH 2CH2CH3 , -OCH 2(CH 3) 2, -CH 2-CH2 -0-CH3

, -NHCH 3 , -N(CH 3) 2, -NHCH 2 CH3 , -N(CH 3)(CH 2 CH3), -CH2 -CH2-NH-CH 3, -CH 2-CH 2

N(CH 3)-CH 3 , -SCH 3 , -SCH 2CH3 , -SCH 2CH 2CH3 , -SCH 2(CH 3) 2, -CH 2-S-CH 2-CH 3, -CH2-CH 2

, -S(=O)-CH 3, -CH 2 -CH 2-S(=0) 2 -CH3 , and up to two heteroatoms may be consecutive, e.g.,

CH 2-NH-OCH 3 .

[0090] Unless otherwise specified, the term "C1-6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms that are connected to the rest of the molecule through an oxygen atom.

The C 1 -6 alkoxy includes Ci-4 alkoxy, C1 -3 alkoxy, C1 -2 alkoxy, C2-6 alkoxy, C2-4 alkoxy, C6

alkoxy, C 5 alkoxy, C4 alkoxy, C3 alkoxy, etc. Examples of C 1-6 alkoxy include, but are not

limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including

n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy,

and neopentyloxy), hexyloxy, etc.

[0091] Unless otherwise specified, the term "C1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms that are connected to the rest of the molecule through an oxygen atom.

The C 1-3alkoxy includes C 1-3alkoxy, C 1-2alkoxy, C2-3 alkoxy, C1 alkoxy, C2 alkoxy, C3 alkoxy,

etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy

(including n-propoxy and isopropoxy), etc.

[0092] Unless otherwise specified, the term "C 1-6 alkylamino" refers to an alkyl group containing 1 to 6 carbon atoms that are connected to the rest of the molecule through an amino

group. The C 1-6 alkylamino includes Ci-4 alkylamino, C1 -3 alkylamino, C1 -2 alkylamino, C2-6

alkylamino, C2-4 alkylamino, C6 alkylamino, C5 alkylamino, C4 alkylamino, C3 alkylamino, C2

alkylamino, etc. Examples of C 1-6 alkylamino include, but are not limited to, -NHCH 3,

N(CH 3 ) 2 , -NHCH 2CH 3, -N(CH 3)CH 2CH3 , -N(CH 2CH 3)(CH 2CH 3), -NHCH 2CH 2CH3 ,

NHCH 2(CH 3) 2 , -NHCH 2CH 2CH2 CH3, etc.

[0093] Unless otherwise specified, the term "C1-3 alkylamino" refers to an alkyl group

containing 1 to 3 carbon atoms that are connected to the rest of the molecule through an amino

group. The C1 -3 alkylamino includes C1 -3 alkylamino, C1 -2 alkylamino, C2-3 alkylamino, C 1

alkylamino, C2alkylamino, C3 alkylamino, etc. Examples of C1-3 alkylamino include, but are not limited to, -NHCH3 , -N(CH 3)2 , -NHCH2 CH3, -N(CH 3)CH 2CH 3, -NHCH2 CH2CH 3,

NHCH2(CH3)2, etc.

[0094] Unless otherwise specified, the term "C 1 6 alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms that are connected to the rest of the molecule through a sulfur

atom. The C 1 .6 alkylthio includes C 1 .4 alkylthio, C 1.3 alkylthio, C 1-2 alkylthio, C2-6 alkylthio,

C 2 -4 alkylthio, C 6 alkylthio, C5 alkylthio, C 4 alkylthio, C3 alkylthio, C2 alkylthio, etc. Examples of C1 .6 alkylthio include, but are not limited to, -SCH 3 , -SCH 2CH 3, -SCH 2 CH2CH3

, -SCH2(CH3)2, etc.

[0095] Unless otherwise specified, the term "C 13 alkylthio" refers to an alkyl group

containing 1 to 3 carbon atoms that are connected to the rest of the molecule through a sulfur

atom. The C 1.3 alkylthio includes C 1 .3 alkylthio, C1 -2 alkylthio, C2-3 alkylthio, C 1 alkylthio,

C2 alkylthio, C3 alkylthio, etc. Examples of C1-3 alkylthio include, but are not limited to,

SCH 3, -SCH 2CH 3, -SCH 2CH 2CH3 , -SCH 2(CH3) 2 , etc.

[0096] Unless otherwise specified, "C 4 -6cycloalkyl" refers to a saturated cyclic hydrocarbon

group consisting of 4 to 6 carbon atoms in monocyclic and bicyclic systems, and the C 4 -6

cycloalkyl includes C 4-5 cycloalkyl, C5-6 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, etc.; it can

be monovalent, divalent, or multivalent. Examples of C 4 .6 cycloalkyl include, but are not

limited to, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0097] Unless otherwise specified, the term "4- to 6-membered heterocyclyl" by itself or in

combination with other terms refers to a saturated cyclic group consisting of 4 to 6 ring atoms,

respectively, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from 0,

S, and N and the rest are carbon atoms, wherein the nitrogen atoms are optionally quaternized,

and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or

2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro

rings, fused rings, and bridged rings. In addition, in the case of the "4- to 6-membered

heterocycloalkyl", the heteroatom may occupy the position where the heterocycloalkyl is

linked to the rest of the molecule. The 4- to 6-membered heterocycloalkyl includes 4- to 5

membered heterocycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 5

to 6-membered heterocycloalkyl, 6-membered heterocycloalkyl, etc. Examples of 4- to 6

membered heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2 piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxolyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

[0098] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5 to 6-membered heteroaryl" in the present disclosure may be used interchangeably, and the term

"5- to 6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms

with conjugated n electronic system, wherein 1, 2, 3, or 4 ring atoms are heteroatoms

independently selected from 0, S, and N, and the rest are carbon atoms. Where the nitrogen

atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized

(i.e., NO and S(O)p, p is 1 or 2). The 5- to 6-membered heteroaryl may be attached to the rest

of the molecule through a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl

includes 5-membered and 6-membered heteroaryl. Examples of the 5- to 6-membered

heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,

etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl,

2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5

oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4

triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl

(including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl,

etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridinyl (including 2-pyridyl, 3-pyridyl, 4

pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

[0099] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific instance of n to

n+m carbons, for example, C1-12 includes C1 , C2, C3, C4 , Cs, C6, C 7 , C8, C9, Cio, Ci, and C 12,

also includes any range from n to n+m, for example, C1I-12 includes C 1 -3, Ci- 6 , Ci-9, C3- 6 , C3-9,

C3-12, C6.9, C6- 12, C9-12, etc.; similarly, n-membered to n+m-membered means that the number

of atoms on the ring is from n to n+m, for example, 3- to 12-membered ring includes 3

membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8 membered ring, 9-membered ring, 0-membered ring, 11-membered ring, and 12-membered ring, also includes any range from n to n+m, such as 3- to 12-membered ring includes 3- to 6 membered ring, 3- to 9-membered ring, 5- to 6-membered ring, 5- to 7-membered ring, 5- to 10-membered ring, 6- to 7-membered ring, 6- to 8-membered ring, 6- to 9-membered ring, and 6- toO -membered ring.

[0100] The term "leaving group" refers to a functional group or atom which can be replaced by another functional group or atom through a substitution reaction (such as nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p toluenesulfonate; acyloxy, such as acetoxy, trifluoroacetoxy.

[0101] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxyl protecting group", or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing the side reactions occurring at the nitrogen of an amino. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4' methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term "hydroxyl protecting group" refers to a protecting group suitable for preventing the side reactions of hydroxyl. Representative hydroxyl protecting groups include, but are not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert butyldimethylsilyl (TBS).

[0102] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred embodiments include but are not limited to the examples of the present disclosure.

[0103] The solvent used in the present disclosure is commercially available.

[0104] The compounds of the present disclosure are named according to the conventional naming principles in the art or by ChemDraw@ software, and the commercially available

compounds use the supplier catalog names.

BRIEF DESCRIPTION OF THE DRAWINGS

[0105] Figure 1 is a graph of repeated experiment I according to an example of the present disclosure;

[0106] Figure 2 is a graph of repeated experiment II according to an example of the present disclosure.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0107] The present disclosure is described in detail by the examples below, but it does not

mean that there are any adverse restrictions on the present disclosure. The present disclosure

has been described in detail herein, and its specific embodiments have also been disclosed; for

one skilled in the art, it is obvious to make various modifications and improvements to the

embodiments of the present disclosure without departing from the spirit and scope of the

present disclosure.

[0108] The experimental materials and reagents used in the following examples can be

obtained from commercially available sources unless otherwise specified.

[0109] Preparation of intermediates

[0110] Reference example 1: Preparation of intermediate I-1

0 0 CI C

H YS|

[0111] To a solution of 7-chloro-1,2,3,4-tetrahydrobenzo[B]azepin-5-one (15 g, 76.7 mmol)

in pyridine (150 mL) was added p-toluenesulfonyl chloride (21.9 g, 115 mmol) at room

temperature. The reaction mixture was reacted at room temperature for 16 hours and

concentrated under reduced pressure. The reactant was poured into water (200 mL), extracted

with ethyl acetate (100 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by silica gel chromatography to obtain intermediate I-1.

[0112] LC-MS(ESI)[M+H]*349.9.

[0113] 'HNMR(400 MHz, CDC 3) 67.66 (d,J=2.4 Hz, 1H), 7.58 (d,J= 8.3 Hz, 2H), 7.47 (dd,J= 8.6,2.5Hz,1H),7.43(d,J= 8.5Hz,1H),7.28(d,J=8.0Hz,2H),3.83(t,J=6.5Hz, 2H), 2.43 (s, 3H), 2.40 - 2.35 (m, 2H), 2.00 - 1.91 (m, 2H).

[0114] Reference example 2: Preparation of intermediate 1-2 0 0 0 0 CI CI

CN N Ys _ YS 1-2

[0115] Intermediate I-1 (37.00 g, 106.00 mmol) was dissolved in anhydrous tetrahydrofuran (350 mL) at 25°C, and sodium hydride (6.36 g, 60% wt, 159.00 mmol) was added thereto in batches in an ice-water bath under argon atmosphere. After cooling and stirring in an ice water bath for 1 hour, dimethyl carbonate (19.08 g, 212.00 mmol) was added thereto, and the reaction mixture was heated to 50°C and stirred for 24 hours. After cooling, the reaction mixture was slowly poured into cold saturated ammonium chloride aqueous solution (500 mL), concentrated to remove most of the tetrahydrofuran, and filtered. The filter cake was washed with clear water, then slurried with petroleum ether, and filtered, and the filter cake was dried under reduced pressure to obtain intermediate 1-2.

[0116] LC-MS (ESI) [M+H]* 408.0.

[0117] Reference example 3: Preparation of intermediate 1-3 0

0 Br N

0 0

N CI

1-2 1-3 Ys

[0118] Intermediate 1-2 (19.00 g, 46.68 mmol) was dissolved in anhydrous N,N dimethylformamide (187 mL) at 25°C, and sodium carbonate (14.84 g, 140.00 mmol) and 2

(2-bromoethyl)isoindoline-1,3-dione (23.71 g, 93.36 mmol) were sequentially added thereto.

The reaction mixture was stirred overnight at 90°C under argon atmosphere. The reaction

mixture was cooled, then diluted with ethyl acetate (500 mL), washed with water (150 mL x

3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered,

and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude

product was purified by silica gel chromatography to obtain intermediate 1-3.

[0119] LC-MS (ESI) [M+H]* 581.2.

[0120] Reference example 4: Preparation of intermediate 1-4

0 0 0

CI CI N C N C

1-3 1-4 t

[0121] Intermediate 1-3 (20.00 g, 34.48 mmol) was dissolved in dimethyl sulfoxide/water

(130 mL/13 mL) at 25°C, and sodium chloride (16.70 g, 28.60 mmol) was added thereto.

After the system was replaced with argon three times, the reaction mixture was stirred at 150°C

for 10 hours under argon atmosphere. The reaction mixture was cooled, then diluted with

ethyl acetate (400 mL), washed with water (150 mL x 3), washed with saturated brine (100

mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under

reduced pressure to obtain a crude product. The crude product was purified by silica gel

chromatography to obtain intermediate 1-4.

[0122] LC-MS (ESI) [M+H]* 523.2.

[0123] Reference example 5: Preparation of intermediate I-5

1ci ci

N ts 1-5 1-4

[0124] Intermediate 1-4 (200 mg, 0.38 mmol) was dissolved in ethanol (7 mL) at 25°C, and

85% hydrazine hydrate (0.35 mL) was added thereto. The reaction mixture was stirred at

35°C for 4 hours, concentrated under reduced pressure to remove most of the ethanol, added with ethyl acetate (50 mL) to dilute, sequentially washed with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of intermediate 1-5. The crude product was directly used in the next reaction step.

[0125] LC-MS (ESI) [M+H]* 375.2.

[0126] Reference example 6: Preparation of intermediate 1-6 N NH CI CI

N N Ys 1-5 s 1-6

[0127] Intermediate 1-5 (170 mg, 0.45 mmol) was dissolved in methanol (10 mL) at 25°C, and sodium borohydride (190 mg, 5.00 mmol) was slowly added thereto under cooling in an

ice-water bath. The reaction mixture was stirred at room temperature for 1 hour, concentrated

under reduced pressure to remove most of the methanol, diluted with ethyl acetate (50 mL),

sequentially washed with water (20 mL x 3) and saturated brine (20 mL), dried over anhydrous

sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain

the crude product of intermediate 1-6. The crude product was directly used in the next reaction

step.

[0128] LC-MS (ESI) [M+H]* 377.2.

[0129] Reference example 7: Preparation of intermediate 1-7 NH NH

N N s 1-6 H

[0130] Intermediate 1-6 (150 mg, 0.40 mmol) was dissolved in anhydrous methanol (20 mL)

at 25°C, and magnesium chips (2.00 g, 83.33 mmol) were added thereto. The reaction

mixture was replaced with nitrogen three times, and stirred overnight at 70°C under nitrogen

atmosphere (balloon). After cooling, the reaction mixture was filtered with diatomite. The

filtrate was concentrated to dryness, added with a mixture of dichloromethane/methanol (10/1,

50 mL) to dissolve, washed with saturated ammonium chloride aqueous solution (20 mL x 3),

then washed with water (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I 7. The crude product was directly used in the next reaction step.

[0131] LC-MS (ESI) [M+H]* 223.0.

[0132] Reference example 8: Preparation of intermediate 1-8 NH NBoc CI CI

N N H 1-7 H 1-8

[0133] Intermediate 1-7 (85 mg, 0.38 mmol) was dissolved indichloromethane (3 mL) at25°C, and the mixture was sequentially added with triethylamine (121 mg, 1.20 mmol) and di-tert butyl dicarbonate (124 mg, 0.57 mmol), and stirred overnight at room temperature. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (50 mL), washed with dimethylethylenediamine aqueous solution (1 M, 10 mL x 2), then washed with water (20 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I 8. The crude product was directly used in the next reaction step.

[0134] LC-MS (ESI) [M+H-56]* 267.0.

[0135] Reference example 9: Preparation of intermediate 1-9

0 NBoc CI H NO2 N C

1-8 -9

[0136] 2-Methyl-4-nitrobenzoic acid (181 mg, 1.00 mmol) was dissolved in anhydrous dichloromethane (5 mL) at 25°C, and the mixture was sequentially added with N,N dimethylformamide (20 mg) and oxalyl chloride (591 mg, 4.65 mmol) in an ice-water bath under argon atmosphere. The reaction mixture was continued to stir in an ice-water bath for 1 hour, and concentrated to dryness at room temperature to obtain an acid chloride intermediate. The acid chloride was dissolved in anhydrous dichloromethane, and the mixture was slowly added with intermediate 1-8 (110 mg, 0.34 mmol), triethylamine (343 mg, 3.4 mmol), and a solution of p-dimethylaminopyridine (1.83 mg, 0.15 mmol) in dichloromethane (2.5 mL) in an ice-water bath under argon atmosphere, and stirred overnight at 40°C after the addition was completed. The reaction mixture was added with methanol (0.5 mL) to quench, concentrated to dryness under reduced pressure, added with ethyl acetate (50 mL) to dissolve, sequentially washed with water (30 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate '-9.

[0137] LC-MS (ESI) [M+H]f 486.2.

[0138] Reference example 10: Preparation of intermediate 1-10 NBoc NBoc CII

N N

NO2 NH2 0

1-9

[0139] Intermediate 1-9 (37.00 mg, 0.076 mmol) was dissolved in ethanol (5 mL) at 25°C, and the mixture was added with zinc powder (130 mg, 2.00 mmol), replaced with nitrogen three times, and stirred at 70°C for 3 hours under nitrogen atmosphere (balloon). After cooling, the reaction mixture was filtered with diatomite, and the filtrate was concentrated under reduced pressure to dryness to obtain the crude product of intermediate 1-10. Thecrude product was directly used in the next reaction step.

[0140] LC-MS (ESI) [M+H]* 456.4.

[0141] Reference example 11: Preparation of intermediate I-I1

NBoc N Boc

N C N C cl H'c

1-10

[0142] Intermediate 1-10 (33 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL) at 25°C, and the mixture was sequentially added with triethylamine (50 mg, 0.50 mmol) and o toluyl chloride (23.00 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 1 hour, added with methanol (0.5 mL) to quench, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate I-11.

[0143] LC-MS (ESI) [M+H]* 574.3.

[0144] Reference example 12: Preparation of intermediate 1-12 C F3

0/ N "0 1 N 0 NH2 3N H F 3C 1-12

[0145] Methyl 6-aminonicotinate (1.0 g, 6.57 mmol) was dissolved in pyridine (20 mL) at room temperature, and 2-trifluoromethylbenzoyl chloride (1.51 g, 7.25 mmol) was added

thereto. After the addition was completed, the reaction mixture was stirred at room

temperature for 1 hour. The reaction mixture was poured into ice water (100 mL) and

extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water

(50 mL x 5), dried over anhydrous sodium sulfate, and filtered, and the filtrate was

concentrated under reduced pressure. The residue was purified by silica gel chromatography

to obtain intermediate 1-12.

[0146] LC-MS (ESI) [M+H]* 325.0.

[0147] Reference example 13: Preparation of intermediate 1-13 0 0 ½ N. 0 HO -. 0

fN' N I. N' N H HH 1-12 F 3C 1-13 F3C

[0148] Intermediate 1-12 (1.35 g, 4.16 mmol) was dissolved in tetrahydrofuran (10 mL) at

room temperature, and a solution of sodium hydroxide (499 mg, 12.5 mmol) in water (2 mL)

was added thereto. After the addition was completed, the reaction mixture was stirred at 70°C

for 1 hour. After the reaction was completed, the pH of the reaction mixture was adjusted to

5 to 6 with1 N hydrochloric acid. After filtration, the solid was dried to obtain intermediate

1-13.

[0149] LC-MS (ESI) [M+H]* 311.0.

[0150] Reference example 14: Preparation of intermediate 1-14

HO 0

H NBoc NBoc F3C CI CI 1-13 3 C N ~ F3C N0

N H 1-8 1-14

[0151] Intermediate 1-8 (50 mg, 0.16 mmol) was dissolved intetrahydrofuran (1 mL) at25°C, and the mixture was sequentially added with pyridine (0.79 mL, 10.00 mmol), propylphosphonic anhydride (50% wt ethyl acetate solution, 0.79 mL), and intermediate 1-13

(53 mg, 0.17 mmol), and stirred overnight at 65°C in a sealed microwave tube. Aftercooling, the reaction mixture was concentrated to dryness under reduced pressure, dissolved in ethyl

acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (30 mL x 2),

washed with water (20 mL x 2), washed with saturated brine (20 mL), dried over sodium sulfate,

and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product

of intermediate 1-14. The crude product was directly used in the next reaction step.

[0152] LC-MS (ESI) [M+H]* 615.3.

[0153] Reference example 15: Preparation of intermediate 1-15 NH N CI CI

N N S 1-6 Ys 1-15

[0154] Intermediate 1-6 (115 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane

(2 mL) at 25°C, and the mixture was sequentially added with paraformaldehyde (56 mg, 0.62

mmol) and sodium triacetoxyborohydride (20 mg, 0.93 mmol), and stirred overnight at 90°C

under argon atmosphere. The reaction mixture was cooled, added with saturated ammonium

chloride aqueous solution (2 mL) to quench, concentrated under reduced pressure to remove

dichloromethane, added with ethyl acetate (50 mL) to dilute, sequentially washed with water

(30 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered.

The filtrate was concentrated under reduced pressure to obtain a crude product. The crude

product was purified by silica gel chromatography to obtain intermediate 1-15.

[0155] LC-MS (ESI) [M+H]* 391.2.

[01561 Reference example 16: Preparation of intermediate 1-16

N-- N CI CI

N N S 1-15 H I-16

[0157] Intermediate 1-15 (100 mg, 0.26 mmol) was dissolved in anhydrous methanol (20 mL) at 25°C, and magnesium chips (2.00 g, 83.33 mmol) were added thereto. The reaction

mixture was replaced with nitrogen three times and stirred overnight at 70°C under nitrogen

atmosphere. After cooling, the reaction mixture was filtered with diatomite. The filtrate

was concentrated to dryness, added with a mixture of dichloromethane/methanol (10/1, 50mL)

to dissolve, washed with saturated ammonium chloride aqueous solution (20 mL x 3), then

washed with water (20 mL x 2), dried over anhydrous sodium sulfate, andfiltered. The

filtrate was concentrated under reduced pressure to obtain the crude product of intermediate I

16. The crude product was directly used in the next reaction step.

[0158] LC-MS (ESI) [M+H]* 237.2.

[0159] Reference example 17: Preparation of intermediate 1-17

CI H CIH N C'):) NH 2 1-17 tS

[0160] To a solution of methyl 2-amino-5-chlorobenzoate (200 g, 1.08 mol) in pyridine (1000 mL) was added 4-toluenesulfonyl chloride (247 g, 1.30 mol) at room temperature. The

reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was

poured into ice water (1500 mL) and extracted with ethyl acetate (1000 mL x 3). Theorganic

phases were combined, sequentially washed with water (1500 mL) and saturated brine (1500

reduced pressure to remove the organic solvent to obtain a crude product. The crude product

was purified by slurrying with ethyl acetate/petroleum ether (5:95) to obtain intermediate1-17.

[0161] LC-MS(ESI)[M+H]*340.0.

[01621 'HNMR(400 MHz, DMSO-d )6 610.29 (s, 1H), 7.78 (d,J=2.6 Hz, 1H), 7.67 (d,J=

8.3Hz,2H),7.63(dd,J=8.9,2.6Hz,1H),7.46(d,J=8.9Hz,1H),7.36(d,J= 8.1Hz,2H), 3.80 (s, 3H), 2.34 (s, 3H).

[0163] Reference example 18: Preparation of intermediate 1-18

Br CI 0 CI

NH N

1-17 8S |-18

[0164] To a solution of intermediate 1-17 (200 g, 0.589 mol) and ethyl 4-bromobutyrate (121

g, 0.620 mol) in N,N-dimethylformamide (1000 mL) was added cesium carbonate (384 g, 1.18

mol) at room temperature, and the reaction mixture was stirred at 120°C for 2 hours, cooled to

room temperature, poured into ice water (2 L), and extracted with ethyl acetate (1000 mL x 3).

The organic phases were combined, sequentially washed with water (1000 mL x 3) and

saturated brine (1000 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate

was concentrated under reduced pressure to remove the organic solvent to obtain a crude

product. The crude product was purified by slurrying with ethyl acetate/petroleum ether (5:95)

to obtain intermediate 1-18.

[0165] LC-MS(ESI)[M+H]*454.1.

[01661 'HNMR(400 MHz, DMSO-d) 67.79 (d,J= 2.6 Hz, 1H), 7.61 (dd,J= 8.6,2.6 Hz, 1H), 7.39 (s, 4H), 6.97 (d, J= 8.6 Hz, 1H), 4.01 (q, J= 7.1 Hz, 2H), 3.76 (s, 3H), 3.70 (m, 1H),

3.45 (m, 1H), 2.45 - 2.32 (m, 5H), 1.71 - 1.60 (m, 2H), 1.14 (t, J= 7.1 Hz, 3H).

[0167] Reference example 19: Preparation of intermediate 1-19

CI oCl N +s N 1-18 1-19 YS

[0168] To toluene (1.6 L) was added potassium tert-butoxide (69.0 g, 0.615 mol) at room

temperature, and the mixture was heated to 70°C, stirred for 30 minutes, and then added with

intermediate 1-18 (186 g, 0.410 mol). The reaction mixture was stirred at 100°C for 1 hour,

cooled to room temperature, added with water (1 L), and extracted with ethyl acetate (1 L x 2).

The organic phases were combined, washed with saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-19. The crude product was directly used in the next reaction step without purification.

[0169] Reference example 20: Preparation of intermediate 1-20

O Br 0/

CI CII

Ts N Ts 1-19 1-20

[0170] Intermediate 1-19 (5.00 g, 11.87 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) at 25°C, and the mixture was cooled in an ice-water bath under argon atmosphere, and slowly added with 60% sodium hydride (0.95 g, 23.74 mmol). After cooling and stirring in an ice-water bath for 0.5 hours, methyl bromoacetate (3.63 g, 23.74 mmol) was added thereto, and the reaction mixture was stirred overnight at room temperature, poured into cold saturated ammonium chloride aqueous solution (100 mL), concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain intermediate 1-20.

[0171] LC-MS (ESI) [M+H]* 494.2.

[0172] Reference example 21: Preparation of intermediate 1-21 0 0/ 0 0/

0 0 0 CI CI

N N / Ts Ts 1-20 1-21

[0173] Intermediate 1-20 (5.50 g, 11.16 mmol) was dissolved in dimethyl sulfoxide/water (55 mL/5 mL) at 25°C, and sodium chloride (0.71 g, 12.00 mmol) was added thereto. After the system was replaced with argon three times, the reaction mixture was stirred at 150°C for 10 hours under argon atmosphere. The reaction mixture was cooled, then diluted with ethyl acetate (200 mL), washed with water (50 mL x 3), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain intermediate1-21.

[0174] LC-MS (ESI) [M+H]7 422.0.

[0175] Reference example 22: Preparation of intermediate 1-22 0 0/ OH 0 OH

CI CI

N N Ts Ts 1-21 1-22

[0176] Intermediate 1-21 (1.00 g, 2.38 mmol) was dissolved in anhydrous tetrahydrofuran(15 mL) at 25°C. The system was cooled with an ice-water bath under argon atmosphere, and a solution of lithium borohydride in tetrahydrofuran (1 M, 7.14 mL, 7.14 mmol) was slowly added thereto under stirring. After the addition was completed, the reaction mixture was naturally warmed to room temperature, stirred for about 3 hours, poured into cold saturated ammonium chloride aqueous solution (100 mL), concentrated under reduced pressure to remove most of the tetrahydrofuran, and extracted with a mixture of dichloromethane/methanol (10/1,50mLx2). The organic phases were combined, washed with water (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-22. The crude product was directly used in the next reaction step without purification.

[0177] LC-MS (ESI) [M-H 20+H]f 378.2.

[0178] Reference example 23: Preparation of intermediates I-23A and I-23B OH OH 0 0 CI CI CI

N N N Ts Ts Ts 1-22 1-23A I-23B

[0179] Intermediate 1-22 (900 mg, 2.27 mmol) was dissolved in anhydrous dichloromethane (30 mL) at 25°C, and boron trifluoride diethyl etherate (1.26 mL, 10 mmol) was added thereto. After the system was replaced with argon three times, the reaction mixture was stirred at 40°C for 16 hours under argon atmosphere, and concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain intermediate I-23A (Rt = 1.342 min) and intermediate I-23B (Rt = 1.321 min).

[0180] LCMS analysis method: Chromatographic column: Infinitylab Poroshell 120 EC-C18 3.0 x 30 mm, 1.9 pm

[0181] Mobile phase: A: water (0.01% trifluoroacetic acid) B: acetonitrile (0.01%

trifluoroacetic acid)

[0182] Elution gradient: 5% to 95% B, 0.7 minutes; 95% B, 0.8 minutes; then 5% B, 0.5 minutes

[0183] Flow rate: 1.2 mL/min

[0184] Chromatographic column temperature: 40°C

[0185] Mass spectrum scanning range: 100 to 1000

[0186] Intermediate I-23A (Rt = 1.342 min) LC-MS (ESI) [M+H]* 378.0.

[0187] Intermediate I-23B (Rt = 1.321 min) LC-MS (ESI) [M+H]* 378.0.

[0188] Reference example 24: Preparation of intermediate 1-24

0 0

Ts H 1-23A 1-24

[0189] Intermediate I-23A (280.00 mg, 0.74 mmol) was dissolved in anhydrous methanol (20

mL) at 25°C, and magnesium chips (2.00 g, 83.33 mmol) were added thereto. The reaction

was concentrated to dryness under reduced pressure, added with ethyl acetate (100 mL) to

dissolve, washed with saturated ammonium chloride aqueous solution (30 mL x 3), then

washed with water (30 mL x 2), washed with saturated brine (20 mL), dried over anhydrous

sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove

the organic solvent to obtain the crude product of intermediate 1-24. The crude product was

directly used in the next reaction step without purification.

[0190] LC-MS (ESI) [M+H]* 224.0.

[0191] Reference example 25: Preparation of intermediate 1-25

C HO NO2 CI

H 1-24 / NO2 1-25

[0192] 2-Methyl-4-nitrobenzoic acid (168 mg, 0.93 mmol) was dissolved in anhydrous

dichloromethane (5 mL) at 25°C, and the mixture was sequentially added with N,N

dimethylformamide (20 mg) and oxalyl chloride (591 mg, 4.65 mmol) in an ice-water bath

under argon atmosphere. The reaction mixture was continued to stir in an ice-water bath for

1 hour and concentrated to dryness at room temperature to obtain an acid chloride intermediate.

The acid chloride was dissolved in anhydrous dichloromethane, and the mixture was slowly

added with intermediate 1-24 (70 mg, 0.31 mmol), triethylamine (310 mg, 3.10 mmol), and a

solution of p-dimethylaminopyridine (1.83 mg, 0.15 mmol) in dichloromethane (2 mL) in an

ice-water bath under argon atmosphere, and stirred overnight at 40°C after the addition was

completed. After the reaction was completed, the reaction mixture was added with methanol

(0.5 mL) to quench, concentrated to dryness under reduced pressure, added with ethyl acetate

(50 mL) to dissolve, sequentially washed with water (30 mL x 2) and saturated brine (20 mL),

dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under

reduced pressure and the residue was purified by silica gel chromatography to obtain

intermediate 1-25.

[0193] LC-MS (ESI) [M+H]* 387.2.

[0194] Reference example 26: Preparation of intermediate 1-26

S 0

0 \/NO 2 NH2

1-25 1-26

[0195] Intermediate 1-25 (40 mg, 0.10 mmol) was dissolved in ethanol (5 mL) at25°C, and

the mixture was added with zinc powder (130 mg, 2.00 mmol), replaced with nitrogen three

times, and stirred at 70°C for 3 hours under nitrogen atmosphere. After cooling, the reaction mixture was filtered with diatomite, and thefiltrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-26. The crude product was directly used in the next reaction step without purification.

[0196] LC-MS (ESI) [M+H]* 357.2.

[0197] Reference example 27: Preparation of intermediate 1-27 0 CI CI &o

N -~N

Ts H 1-23B 1-27

[0198] Intermediate I-23B (280 mg, 0.74 mmol) was dissolved in anhydrous methanol (20 mL) at 25°C, and magnesium chips (2.00 g, 83.33 mmol) were added thereto. The reaction mixture was replaced with nitrogen three times and stirred overnight at 70°C under nitrogen atmosphere. After cooling, the reaction mixture was filtered with diatomite. The filtrate was concentrated to dryness under reduced pressure, added with ethyl acetate (100 mL) to dissolve, washed with saturated ammonium chloride aqueous solution (30 mL x 3), then washed with water (30 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-27. The crude product was directly used in the next reaction step without purification.

[0199] LC-MS (ESI) [M+H]* 224.0.

[0200] Reference example 28: Preparation of intermediate 1-28

C HO NO2 CI N"C NN

O NO2 1-27 1-28

[0201] 2-Methyl-4-nitrobenzoic acid (168 mg, 0.93 mmol) was dissolved in anhydrous dichloromethane (5 mL) at 25°C, and the mixture was sequentially added with N,N dimethylformamide (20 mg) and oxalyl chloride (591 mg, 4.65 mmol) in an ice-water bath under argon atmosphere. The reaction mixture was continued to stir in an ice-water bath for 1 hour, and concentrated to dryness at room temperature to obtain an acid chloride intermediate.

The acid chloride was dissolved in anhydrous dichloromethane, and the mixture was slowly added with intermediate 1-27 (50 mg, 0.22 mmol), triethylamine (310 mg, 3.10 mmol), and a solution of p-dimethylaminopyridine (1.83 mg, 0.15 mmol) in dichloromethane (2 mL) in an ice-water bath under argon atmosphere, and stirred overnight at 40°C after the addition was completed. After the reaction was completed, the reaction mixture was added with methanol (0.5 mL) to quench, concentrated to dryness under reduced pressure, added with ethyl acetate (50 mL) to dissolve, sequentially washed with water (30 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain intermediate 1-28.

[0202] LC-MS (ESI) [M+H]* 387.2.

[0203] Reference example 29: Preparation of intermediate 1-29

CI CI 0 0

/ NO2 O NH2

1-28 1-29

[0204] Intermediate 1-28 (30 mg, 0.078 mmol) was dissolved in ethanol (5 mL) at 25°C, and the mixture was added with zinc powder (130 mg, 2.00 mmol), replaced with nitrogen three times, and stirred at 70°C for 3 hours under nitrogen atmosphere. After cooling, the reaction mixture was filtered with diatomite, and thefiltrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-29. The crude product was directly used in the next reaction step without purification.

[0205] LC-MS (ESI) [M+H]* 357.2.

[0206] Reference example 30: Preparation of intermediate 1-30 OHOH

CI _ _ _ _N CI

NN Ys 1-19 s 1-30

[0207] Intermediate 1-19 (5.0 g, 11.85 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. To the reaction system was added sodium borohydride (8.78 g, 232.09 mmol) under nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 24 hours, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-30.

[0208] LC-MS (ESI) [M+H]* 382.2.

[0209] Reference example 31: Preparation of intermediate 1-31 OH OMsOH CI CI

N N Ys 1-30 Ys 1-31

[0210] Intermediate 1-30 (3.54 g, 9.29 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and methylsulfonyl chloride (1.16 g, 10.22 mmol), triethylamine (1.41 g, 13.93 mmol) were sequentially added thereto, and the reaction mixture was stirred at 0°C for 1 hour under argon atmosphere, diluted with water (50 mL), and extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-31. The crude product was directly used in the next reaction step without purification.

[0211] Reference example 32: Preparation of intermediate 1-32 OMsO

CI CI N N ts 1-31 s 1-32

[0212] Intermediate 1-31 (3.71 g, 8.08 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature. To the reaction mixture was added 60% sodium hydride (808 mg, 20.20 mmol) under argon atmosphere, and the reaction mixture was stirred at room temperature for 16 hours, added with water (50 mL) to quench, and extracted with ethyl acetate (30 mL x 2).

The organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-32.

[0213] LC-MS (ESI) [M+Na]* 386.0.

[0214] Reference example 33: Preparation of intermediate 1-33 0 0 _ _ S CI N N 1-32 H1-33

[0215] Intermediate 1-32 (2.34 g, 6.43 mmol) was dissolved in methanol (50 mL) at room temperature. Magnesium chips (1.54 g, 64.40 mmol) were added thereto under nitrogen atmosphere, and the reaction mixture was stirred at 70°C for 1 hour. The reaction system was cooled to room temperature, diluted with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (30 mL x 2), and the organic phases were combined, washed with saturated ammonium chloride aqueous solution (30 mL x 2), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-33.

[0216] LC-MS (ESI) [M+H]f 210.0.

[0217] Reference example 34: Preparation of intermediate 1-34 CI

C 0 NO2C

N2 1-33 1-34

[0218] Intermediate 1-33 (400 mg, 1.91 mmol) was dissolved in dichloromethane (20 mL) at room temperature. NN-Diisopropylethylamine (740 mg, 5.74 mmol) was added thereto at room temperature under nitrogen atmosphere. The above reaction mixture was added with 2 methyl-4-nitrobenzoyl chloride (455 mg, 2.29 mmol), stirred at room temperature for 16 hours, diluted with water (20 mL), and extracted with dichloromethane (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-34.

[0219] LC-MS (ESI) [M+H]* 373.2.

[0220] Reference example 35: Preparation of intermediate 1-35

CI CI

NO 2 NH 2 1-34 1-35

[0221] Intermediate 1-34 (100 mg, 0.27 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and zinc powder (349 mg, 5.37 mmol) and ammonium chloride (284 mg, 5.37 mmol) were added thereto under nitrogen atmosphere, and the reaction mixture was stirred at 80°C for 1 hour, filtered, and concentrated to dryness under reduced pressure to obtain the crude product of intermediate 1-35. The crude product was directly used in the next reaction step without purification.

[0222] LC-MS (ESI) [M+H]* 343.2.

[0223] Reference example 36: Preparation of intermediate 1-36 0 ....... Ock N

CI C

TN N Tss "

1-19 1-36

[0224] Intermediate 1-19 (2.00 g, 4.75 mmol) was dissolved inpyridine (10 mL) at25°C, and methoxyamine hydrochloride (0.79 g, 9.50 mmol) was added thereto. The reaction mixture was stirred in a sealed microwave tube at 80°C for 10 hours, then concentrated, diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride aqueous solution (50 mL x 2), washed with water (50 mL x 2), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-36. The crude product was directly used in the next reaction step without purification.

[0225] LC-MS (ESI) [M+H]* 451.2.

[0226] Reference example 37: Preparation of intermediate 1-37

0'N HOI NH 2 NH

N Ts Ts 1-37 1-36

[0227] Intermediate 1-36 (2.20 g) was dissolved in borane tetrahydrofuran (24.50 mL, 22.05 mmol) at 25°C, and the mixture was replaced with argon three times and stirred overnight at 50°C under argon atmosphere. Under cooling in an ice-water bath, the mixture was added with methanol dropwise until no bubbling was observed, and concentrated under reduced pressure to obtain the crude product of intermediate 1-37. The crude product was directly used in the next reaction step without purification.

[0228] LC-MS (ESI) [M+H]* 381.2.

[0229] Reference example 38: Preparation of intermediate 1-38 NH 2 NHBoc HO HOjC

IN N Ts 1-37 Ts -38

[0230] Intermediate 1-37 (2.50 g) was dissolved in dichloromethane (20 mL) at 25°C, and triethylamine (1.48 g, 14.70 mmol), di-tert-butyl dicarbonate (2.20 g, 10.09 mmol) were sequentially added thereto, and stirred overnight at 25°C. The reaction mixture was concentrated, dissolved in ethyl acetate (100 mL), washed with dimethylethylenediamine aqueous solution (1 M, 30 mL x 2), washed with water (30 mL), washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-38. The crude product was directly used in the next reaction step without purification.

[0231] LC-MS (ESI) [M+H-56]* 425.3.

[0232] Reference example 39: Preparation of intermediate 1-39 NHBoc NHBoc HO CI MsO CI

Ts 1-38 Ts 1-39

[0233] Intermediate 1-38 (2.50 g) was dissolved in anhydrous dichloromethane (20 mL) at 25°C, and the mixture was added with triethylamine (1.00 g, 9.90 mmol), and then dropwise

added with methanesulfonyl chloride (0.82 g, 7.13 mmol) in ice-water bath under argon

atmosphere. The reaction mixture was stirred at 25°C for 1 hour, added dropwise with

methanol (1 mL) to quench, concentrated under reduced pressure, dissolved in ethyl acetate

(100 mL), washed with saturated sodium bicarbonate aqueous solution (30 mL x 2), washed

with water (30 mL), washed with saturated sodium chloride aqueous solution (30 mL), dried

over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced

pressure to remove the organic solvent to obtain a crude product. The crude product was

purified by silica gel chromatography to obtain intermediate 1-39.

[0234] LC-MS (ESI) [M+H-100]* 459.0.

[0235] Reference example 40: Preparation of intermediate 1-40 NHBoc NBoc MsO CI CI

N N Ts Ts 1-39 1-40

[0236] Intermediate 1-39 (2.00 g, 3.58 mmol) was dissolved in anhydrous tetrahydrofuran(10 mL) at 25°C, and the mixture was added with 60% of sodium hydride (2.90 g, 72.5 mmol),

replaced with argon three times at 70°C and stirred overnight. The reaction mixture was

cooled, poured into cold saturated ammonium chloride aqueous solution (20 mL), concentrated

under reduced pressure to remove most of the tetrahydrofuran, and extracted with ethyl acetate

(50 mL x 2). The organic phases were combined, washed with water (30 mL x 2), washed

with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate,

and filtered. The filtrate was concentrated under reduced pressure to remove the organic

solvent to obtain a crude product. The crude product was purified by silica gel

chromatography to obtain intermediate 1-40.

[0237] LC-MS (ESI) [M+H-56]* 406.90.

[02381 Reference example 41: Preparation of intermediate 1-41 NBoc NH CI CI

N N Ts Ts 1-40 1-41

[0239] Intermediate 1-40 (0.45 g, 0.97 mmol) was dissolved in a solution of trifluoroacetic acid in dichloromethane (1/10, 5 mL) at25°C, and the mixture was stirred for 1 hour andpoured

into cold saturated sodium bicarbonate aqueous solution (50 mL), concentrated at room

temperature to remove most of the dichloromethane, and extracted with ethyl acetate (30 mL

x 2). The organic phases were combined, washed with water (20 mL x 2), washed with

saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and

filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent

to obtain the crude product of intermediate 1-41. The crude product was directly used in the

next reaction step without purification.

[0240] Reference example 42: Preparation of intermediate 1-42

NH NH CI CI

N N Ts 1-41 H -42

[0241] Intermediate 1-41 (0.31 g, 0.86 mmol) was dissolved in anhydrous methanol (20 mL)

at 25°C, and the mixture was added with magnesium chips (1.20 g, 50.00 mmol), replaced with

argon three times, and stirred overnight at 70°C under argon atmosphere. After cooling, the

reaction mixture was filtered with diatomite. The filtrate was concentrated, added with

dichloromethane/methanol (10/1, 100 mL) to dilute, washed with saturated ammonium

chloride aqueous solution (30 mL x 2), washed with water (30 mL x 2), washed with saturated

sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered.

The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain

the crude product of intermediate 1-42. The crude product was directly used in the next

reaction step without purification.

[02421 LC-MS (ESI) [M+H]* 208.8.

[0243] Reference example 43: Preparation of intermediate 1-43

NH NBoc CI CI

N N H 1-42 1-43

[0244] Intermediate 1-42 (0.15 g) was dissolved in dichloromethane (3 mL) at 25°C, and triethylamine (0.22 g, 2.16 mmol), di-tert-butyl dicarbonate (0.31 g, 1.44 mmol) were

sequentially added thereto. The reaction mixture was stirred at 25°C for 3 hours and

to obtain intermediate 1-43.

[0245] LC-MS (ESI) [M+H]* 309.2.

[0246] Reference example 44: Preparation of intermediate 1-44 HO NBoc NBoc C1 ) N2I C1

N N

1-43 NO2 1-44

[0247] 2-Methyl-4-nitrobenzoic acid (0.58 g, 3.20 mmol) was dissolved in anhydrous

dichloromethane (5 mL) at 25°C, and the mixture was added with a drop of N,N

dimethylformamide, cooled in an ice-water bath under argon atmosphere, slowly added

dropwise with oxalyl chloride (1.63 g, 12.8 mmol), stirred in an ice-water bath for 1 hour, and

then concentrated to dryness at room temperature to obtain an acid chloride intermediate. The

acid chloride intermediate was dissolved in anhydrous dichloromethane (5 mL), and

triethylamine (2.56 g, 25.60 mmol), 4-dimethylaminopyridine (2.44 mg, 0.02 mmol), and

intermediate 1-43 (100 mg, 0.32 mmol) were added thereto in an ice-water bath under argon

atmosphere. The reaction mixture was stirred overnight at 40°C, then cooled to room

temperature, added dropwise with methanol (2 mL) to quench, concentrated under reduced

pressure, diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate

aqueous solution (20 mL x 2), washed with water (20 mL), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate '-44.

[0248] LC-MS (ESI) [M+H]* 471.8.

[0249] Reference example 45: Preparation of intermediate 1-45 NBoc NBoc CI CI

N N

O NO 2 0 NH 2

1-44 1-45

[0250] Intermediate 1-44 (63 mg, 0.13 mmol) was dissolved intetrahydrofuran (5 mL) at25°C, and the mixture was sequentially added with zinc powder (87 mg, 1.30 mmol) and ammonium chloride (35 mg, 0.65 mmol), and stirred at 70°C for 5 hours under argon atmosphere. After cooling, the reaction mixture was filtered with diatomite. The filtrate was concentrated under reduced pressure, added with ethyl acetate (50 mL) to dissolve, washed with water (20 mL x 2), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product of intermediate 1-45. The crude product was directly used in the next reaction step without purification.

[0251] LC-MS (ESI) [M+H]* 441.8.

[0252] Reference example 46: Preparation of intermediate 1-46 CI NBoc NBoc

Cl Cl C N - N N Ci / NH 2 O/H

1-45 1-46

[0253] Intermediate 1-45 (50 mg) was dissolved in dichloromethane (2 mL) at 25°C, and triethylamine (33 mg, 0.33 mmol), o-chlorobenzoyl chloride (50% wt ethyl acetate solution, 0.79 mL) were sequentially added thereto. The reaction mixture was stirred for 1 hour under argon atmosphere at 25°C, added with 4-aminobutanol (0.5 mL), continued to stir for 15 minutes at 25°C, added with dichloromethane (30 mL) to dilute, washed with water (20 mL x

2), washed with saturated sodium chloride aqueous solution (20 mL), dried over anhydrous

the organic solvent to obtain the crude product of intermediate 1-46. The crude product was

directly used in the next reaction step without purification.

[0254] LC-MS (ESI) [M+H]* 580.2.

[0255] Reference example 47: Preparation of intermediate 1-47 NH NFmoc CI CI

N N H H

1-7 1-47

[0256] Intermediate 1-7 (7.30 g, 32.89 mmol) and triethylamine (10.10 g, 100.00 mmol) were

dissolved in anhydrous dichloromethane (100 mL) at 25°C. The mixture was slowly added

with 9-fluorenylmethyl chloroformate (12.73 g, 49.33 mmol) in an ice-water bath under argon

protection and stirred at 25°C for 16 hours. The reaction mixture was concentrated under

reduced pressure at room temperature, slurried with petroleum ether, and filtered. The filter

cake was washed with water (20 mL), and dried under reduced pressure to obtain intermediate

1-47.

[0257] LC-MS (ESI) [M+H]* 444.8.

[0258] Reference example 48: Preparation of intermediates I-48A and I-48B OH

0 N 0 CF3 N NFmoc /-NFmoc N~rmoc H CI- CI CI 1-131 N-C F3 C N C F3 C N HOO H0 \ N \/ NH \ /

N H \/N 1-47 1-48A (trans) 1-48B (cis)

[0259] Intermediate 1-47 (4.70 g, 10.58 mmol) was dissolved in anhydrous tetrahydrofuran

(35 mL) at 25°C, and the mixture was sequentially added with pyridine (8.37 g, 106.00 mmol),

intermediate 1-13 (4.92 g, 15.87 mmol), and propylphosphonic anhydride (50% wt ethyl acetate solution, 20.00 g, 31.74 mmol), stirred overnight at 65°C under argon atmosphere. After cooling, the reaction mixture was concentrated to remove most of the tetrahydrofuran, diluted with ethyl acetate (150 mL), sequentially washed with 1 N hydrochloric acid (100 mL x 2), washed with saturated sodium bicarbonate aqueous solution (100 mL x 3), washed with water

(100 mL), washed with saturated sodium chloride aqueous solution (100 mL), dried over

anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure

to remove the organic solvent to obtain a crude product. The crude product was purified by

silica gel chromatography to obtain intermediate I-48A (Rt = 1.541 min) and intermediate I

48B (Rt = 1.508 min).

[0260] LCMS analysis method: Chromatographic column: Waters aquity UPLC CSH 2.1 x 50 mm, 1.7 pm

[0261] Mobile phase: A: water (0.01% trifluoroacetic acid) B: acetonitrile (0.01%

trifluoroacetic acid)

[0262] Elution gradient: 5% to 95% B, 0.7 minutes; 95% B, 0.8 minutes; then 5% B, 0.5 minutes

[0263] Flow rate: 1.0 mL/min

[0264] Chromatographic column temperature: 60°C

[0265] Mass spectrum scanning range: 100 to 1000

[0266] Intermediate I-48A (Rt = 1.541 min) LC-MS (ESI) [M+H]* 737.3.

[0267] Intermediate I-48B (Rt = 1.508 min) LC-MS (ESI) [M+H]* 737.3.

[0268] Reference example 49: Preparation of intermediate 1-49 0 C1 O2N CI O0C CI

N02

1-49

[0269] To a solution of p-chloronitrobenzene (10.00 g, 63.47 mmol) in N,N dimethylformamide (300 mL) was added potassium tert-butoxide (17.81 g, 158.68 mmol) at

5°C, and the mixture was stirred for 30 minutes and then added with ethyl chloroacetate (8.56

g, 69.82 mmol). The reaction mixture was stirred at -5°C for 1 hour under nitrogen atmosphere, poured into water (1000 mL), extracted with ethyl acetate (200 mL x 4). The organic phases were combined, washed with saturated brine (800 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-49.

[0270] LC-MS (ESI) [M+H]* 244.0.

[0271] Reference example 50: Preparation of intermediate I-50 CI CI

0

NO 2 0O 2

1-49 1-50

[0272] To a solution of intermediate 1-49 (12.00 g, 49.25 mmol) in ether (200 mL) was added diisobutylaluminum hydride (1.5 M in THF, 65.67 mL, 98.50 mmol) under nitrogen

atmosphere at -78°C, and the reaction mixture was stirred at -78°C for 1 hour. The reaction

mixture was warmed to 0°C, added dropwise with water (4 mL) while stirring, then added with

15% sodium hydroxide aqueous solution (4 mL), and finally added with water (10 mL),

warmed to room temperature and stirred for 15 minutes. An appropriate amount of anhydrous

sodium sulfate was added thereto, and the reaction mixture was stirred for 15 minutes, and then

to obtain intermediate I-50.

[0273] LC-MS (ESI) [M+H]* 200.0.

[0274] Reference example 51: Preparation of intermediate 1-51

0

CI 2 :_;NO CI NO 2 1-50 1-51

[0275] To a solution of intermediate 1-50 (7.20 g, 36.07 mmol) in toluene (200 mL) was added

methyl (triphenylphosphoranylidene)acetate (12.06 g, 32.07 mmol) at 25°C. The reaction mixture was stirred at 110°C for 3 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-51.

[0276] Reference example 52: Preparation of intermediate 1-52

NBn NO- 2

NBn C1 NO 2 CI~ ~1-52 0 _ 1-51

[0277] To a solution of intermediate I-51 (7.70 g, 30.12 mmol) indichloromethane (150 mL) was added trifluoroacetic acid (10 mL) at 25°C, and then N-(methoxymethyl)-N

(trimethylsilylmethyl)benzylamine (20.34 g, 85.66 mmol) was added dropwise thereto, and the

reaction mixture was stirred at 25°C for 12 hours, and concentrated under reduced pressure to

remove the organic solvent to obtain a crude product. The crude product was purified by

silica gel chromatography to obtain intermediate 1-52.

[0278] LC-MS (ESI) [M+H]* 389.2.

[0279] Reference example 53: Preparation of intermediate 1-53

NO2 NH 2

CI NBn CI NBn

1-52 0 1-53 0A

[0280] To a mixture of intermediate 1-52 (2.8 g, 7.20 mmol) and ammonium chloride (3.08 g, 57.61 mmol) in methanol (60 mL)/water (20 mL) was added zinc powder (2.35 g, 36.00

mmol) at 25°C. The reaction mixture was stirred at 70°C for 12 hours under nitrogen

atmosphere. The reaction mixture was cooled to room temperature, and filtered, and the

filtrate was concentrated under reduced pressure, and purified by silica gel chromatography to

obtain intermediate 1-53.

[0281] LC-MS (ESI) [M+H]* 359.2.

[0282] Reference example 54: Preparation of intermediate 1-54

NH 2

CI NBn CI NBn

1-53 O O 1-54 HOXO

[0283] To a mixture of intermediate 1-53 (2.30 g, 6.41 mmol) in tetrahydrofuran (10 mL)/methanol (10 mL)/water (10 mL) was added potassium hydroxide (1.08 g, 19.29 mmol)

at 25°C. The reaction mixture was stirred at 25°C for 12 hours under nitrogen atmosphere.

The reaction mixture was adjusted to acidic (pH = 5 to 6) with 1 N hydrochloric acid and

extracted with ethyl acetate (30 mL x 4). The organic phases were combined, washed with

saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. Thefiltratewas

concentrated under reduced pressure to remove the organic solvent to obtain intermediate 1-54.

[0284] LC-MS (ESI) [M+H]* 345.2.

[0285] Reference example 55: Preparation of intermediate 1-55 NH 2 H O N CI CI NBn C H N 1-54 HO O 1-55 Bn

[0286] To a solution of intermediate 1-54 (2.00 g, 5.80 mmol) in dichloromethane (60 mL)

was added N,N-diisopropylethylamine (2.25 g, 17.40 mmol) at 25°C, and then 0

(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (3.72 g, 11.6 mmol) was

added thereto. The reaction mixture was stirred at 25°C for 12 hours under nitrogen

atmosphere, and concentrated under reduced pressure to remove the organic solvent to obtain

a crude product. The crude product was purified by silica gel chromatography to obtain

intermediate 1-55.

[0287] LC-MS (ESI) [M+H]* 327.2.

[0288] Reference example 56: Preparation of intermediate 1-56 H O H N N

Ci1 H C1 ""A H H N N 1-55 Bn 1-56 Bn

[0289] To a solution of intermediate 1-55 (1.78 g, 5.45 mmol) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (27.23 mL, 27.23 mmol, 1 M in THF) in an ice-water bath

under nitrogen atmosphere, and the reaction mixture was stirred at 0°C for 1 hour, sequentially

added with water (4 mL), 15% sodium hydroxide solution (4 mL), and water (10 mL) while

stirring, and filtered after stirring for 15 minutes. The filtrate was extracted with ethyl acetate

(30 mL x 4). The organic phases were combined, washed with saturated brine (100 mL),

was purified by silica gel chromatography to obtain intermediate I-56.

[0290] Reference example 57: Preparation of intermediate 1-57 Bn H N N H H H 'e CI _ __ _ _ ,__ Hon

N N H H 1-56 1-57

[0291] To a 100 mL high pressure reactor was added intermediate 1-56 (250 mg, 0.799 mmol),

palladium carbon (10%, water content of 50%, 200 mg), and methanol (20 mL), and the

reaction mixture was replaced with hydrogen twice, stirred overnight at room temperature

under hydrogen atmosphere (1 MPa). The mixture was filtered, and the filtrate was

concentrated under reduced pressure to obtain intermediate I-57.

[0292] LC-MS (ESI) [M+H]* 189.1.

[0293] Reference example 58: Preparation of intermediate 1-58 H Boc N N H H H'" H-

N N H H 1-57 1-58

[0294] Intermediate 1-57 (110 mg, 0.584 mmol) and triethylamine (295 mg, 2.92 mmol) were

mixed in dichloromethane (5 mL), and di-tert-butyl dicarbonate (153 mg, 0.701 mmol) was

added thereto at room temperature. The reaction mixture was stirred at room temperature for

2 hours. The mixture was concentrated and purified by silica gel chromatography to obtain

intermediate I-58.

[0295] LC-MS (ESI) [M+H]* 289.2.

[02961 Reference example 59: Preparation of intermediate 1-59 Boc Boc N N H H

H H 1-58 1-59

[0297] Intermediate 1-58 (120 mg, 0.416 mmol), copper chloride dihydrate (213 mg, 1.25 mmol), and lithium chloride (53 mg, 1.25 mmol) were dissolved in ethanol (5 mL) at room

temperature. The reaction mixture was heated to 80°C, stirred for 6 hours, then cooled to

room temperature, and concentrated under reduced pressure to remove the solvent. The

residue was diluted with ethyl acetate (10 mL), poured into water (50 mL), added with

ammonia water (2 mL), and extracted with ethyl acetate (10 mL x 4). The organic phases

were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate,

solvent to obtain a crude product. The crude product was purified by silica gel

chromatography to obtain intermediate I-59.

[0298] LCMS (ESI) [M+H+MeCN]* 364.3.

[0299] Reference example 60: Preparation of intermediate 1-60 HO F3C -N Boc Boc Ho N H H 1-13 H... CI

H N/

1-59 H |-60

[0300] Intermediate 1-13 (38.5 mg, 0.124 mmol) was dissolved inN,N-dimethylacetamide (2

mL) at room temperature, and the mixture was cooled to 0°C, and added with thionyl chloride

(14.8 mg, 0.124 mmol) under argon atmosphere. The reaction mixture was stirred at room

temperature for 1 hour, added with intermediate 1-59 (20.0 mg, 0.062 mmol), and continued to

stir at room temperature for 16 hours. The reaction mixture was poured into saturated sodium

bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was purified by silica gel chromatography to obtain intermediate 1-60.

[0301] LC-MS(ESI)[M+H]*615.1.

[0302] Preparation of examples:

[0303] Example 1: Preparation of compound 1 NBoc NH CI CI

N N

H H/ 1-11 Compound1

[0304] Intermediate I-11 (38 mg, 0.066 mmol) was dissolved in a solution of hydrogen chloride in methanol (3 M, 2 mL) at 25°C. The reaction mixture was stirred at room temperature for 1 hour, concentrated to dryness, and purified by preparative HPLC (formic acid system) to obtain compound 1.

[0305] LC-MS (ESI) [M+H]* 474.2.

[0306] 'H NMR (400 MHz, DMSO-d) 6 10.42 - 10.23 (m, 1H), 7.82 - 7.18 (m, 7H), 7.09

(dd, J= 8.3, 2.5 Hz, 1H), 6.90 - 6.43 (m, 2H), 4.94 - 4.72 (m, 1H), 4.30 (s, 1H), 3.15 (m, 3H),

2.73 - 2.62 (m, 1H), 2.43 - 2.27 (m, 6H), 2.27 - 1.98 (m, 2H), 1.75 (m, 3H).

[0307] Example 2: Preparation of compound 2 NBoc NH CI CI

N F3 C N 0 F 3C

1-14 Compound 2

[0308] Intermediate 1-14 (30 mg, 0.049 mmol) was dissolved in a solution of hydrogen chloride in methanol (3 M, 3 mL) at 25°C. The reaction mixture was stirred at room temperature for 1 hour, concentrated to dryness, and purified by preparative HPLC (formic acid system) to obtain compound 2.

[0309] LC-MS (ESI) [M+H]* 515.2.

[0310] 'H NMR (400 MHz, DMSO-d) 611.18 (s, 1H), 8.10 -7.95 (m, 2H), 7.88 - 7.54 (m, 6H), 7.25 - 7.06 (m, 1H), 6.95 (d, J= 8.4 Hz, 1H), 4.89 (d, J= 13.5 Hz, 1H), 4.39 (s, 1H), 3.17

(s, 2H), 2.73 - 2.67 (m, 1H), 2.54 (m, 1 H), 2.27 - 2.01 (m, 2H), 1.85 (m, 2H), 1.67 (m, 1H).

[0311] Example 3: Preparation of compounds 3A and 3B 0

HO N 0

N N N N

CII1F 3C C- -CI F3CCI F3 1-13 1 N H 0 \15N- 0 N 1-16 N H / N H

/ Compound 3A Compound 3B

[0312] Intermediate 1-16 (70 mg, 0.30 mmol) was dissolved intetrahydrofuran (1 mL) at25°C.

The mixture was added with pyridine (0.79 mL, 10 mmol), propylphosphonic anhydride (50%

wt ethyl acetate solution, 0.79 mL), and intermediate 1-7 (101 mg, 0.33 mmol), sealed in a

microwave tube, and stirred at 65°C overnight. After cooling, the reaction mixture was

concentrated to dryness under reduced pressure, dissolved in ethyl acetate (50 mL), washed

with water (20 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium

sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude

product. The crude product was purified by preparative HPLC (formic acid system) to obtain

compound 3A (Rt = 1.023 min) and compound 3B (Rt = 1.039 min).

[0313] LCMS analysis method: Chromatographic column: Infinitylab Poroshell 120 EC-C18

3.0 x 30 mm, 1.9 pm

[0314] Mobile phase: A: water (0.01% trifluoroacetic acid) B: acetonitrile (0.01%

trifluoroacetic acid)

[0315] Elution gradient: 5% to 95% B, 0.7 minutes; 95% B, 0.8 minutes; then 5% B, 0.5

minutes

[0316] Flow rate: 1.2 mL/min

[0317] Chromatographic column temperature: 40°C

[0318] Mass spectrum scanning range: 100 to 1000

[0319] Compound 3A (Rt = 1.023 min):

[0320] LC-MS (ESI) [M+H]* 529.2.

[0321] 'H NMR (400 MHz, DMSO-d) 6 8.15 - 7.95 (m, 2H), 7.92 - 7.34 (m, 6H), 7.15 6.95 (m, 1H), 6.87 - 6.60 (m, 1H), 5.01 (m, 1H), 3.55 - 3.35 (m, 2H), 2.80 - 2.32 (m, 5H),

2.28 - 1.83 (m, 4H), 1.63 (m, 1H).

[0322] Compound 3B (Rt = 1.039 min):

[0323] LC-MS (ESI) [M+H]f 529.2.

[0324] 'H NMR (400 MHz, DMSO-d) 6 8.17 - 7.90 (m, 2H), 7.85 - 7.54 (m, 6H), 7.20

7.00 (m, 1H), 6.90 - 6.60 (m, 1H), 4.70 - 4.50 (m, 1H), 4.15 (m, 1H), 3.98 (d, J= 10.6 Hz,

1H), 2.80 - 2.45 (m, 5H), 2.35 - 2.20 (m, 1H), 2.10 - 1.73 (m, 3H), 1.59 - 1.37 (m, 1H).

[0325] Example 4: Preparation of compound 4 0 0 0 CI CI CI

N N

NH2 0O /

1-26 Compound 4

[0326] Intermediate 1-26 (38 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL) at

25°C. Triethylamine (55 mg, 0.55 mmol), o-toluyl chloride (34 mg, 0.22 mmol) were

sequentially added thereto. The reaction mixture was stirred at room temperature for 1 hour,

added with methanol (1 mL) to quench, concentrated to dryness under reduced pressure, and

purified by preparative HPLC (formic acid system) to obtain compound 4.

[0327] LC-MS (ESI) [M+H]* 475.2.

[0328] 'H NMR (400 MHz, DMSO-d) 6 10.41 - 10.23 (m, 1H), 7.80 - 7.58 (m, 1H), 7.56

7.17 (m, 6H), 7.08 (dd, J= 8.4, 2.6 Hz, 1H), 6.78 (m, 2H), 4.96 - 4.80 (m, 1H), 4.75 (d, J=

7.8 Hz, 1H), 4.14 - 3.88 (m, 2H), 2.73 - 2.61 (m, 1H), 2.45 - 2.30 (m, 6H), 2.30 - 2.03 (m,

2H), 1.84 (m, 3H).

[0329] Example 5: Preparation of compound 5

0 0 CI CI CI

N N

NH2 O 1-29 Compound 5

[0330] Intermediate 1-29 (26 mg, 0.073 mmol) was dissolved in dichloromethane (2 mL) at 25°C. Triethylamine (55 mg, 0.55 mmol), o-toluyl chloride (34 mg, 0.22 mmol) were

purified by preparative HPLC (formic acid system) to obtain compound 5.

[0331] LC-MS (ESI) [M+H]f 475.2.

[0332] 'H NMR (400 MHz, DMSO-d) 6 10.24 (s, 1H), 7.81 - 7.55 (m, 1H), 7.55 - 6.99 (m,

7H), 6.76 (dd, J= 33.3, 8.3 Hz, 2H), 5.37 (d, J= 9.1 Hz, 1H), 4.25 - 3.90 (m, 2H), 3.79 (m,

1H), 2.70 - 2.58 (m, 1H), 2.35 (m, 7H), 2.14 - 1.95 (m, 2H), 1.28 (m, 1H), 1.00 - 0.77 (m, 1H).

[0333] Example 6: Preparation of compound 6 0 0 0 CI CI CI

N N

o NH2 O O/N Oto- H 1-35 Compound 6

[0334] Intermediate 1-35 (90 mg, 0.26 mmol) was dissolved in dichloromethane (10 mL) at

room temperature, and o-toluoyl chloride (60.7 mg, 0.39 mmol) and triethylamine (79.6 mg,

0.79 mmol) were sequentially added thereto. The reaction mixture was stirred at room

temperature for 1 hour, diluted with water (10 mL), and extracted with dichloromethane (20

mL x 2). The organic phases were combined, washed with saturated sodium chloride aqueous

solution (30 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was

concentrated under reduced pressure to remove the organic solvent to obtain a crude product.

The crude product was sequentially purified by silica gel chromatography and preparative

HPLC (formic acid system) to obtain compound 6.

[0335] LC-MS (ESI) [M+H]* 461.2.

[03361 'H NMR (400 MHz, DMSO-d) 6 10.41 - 10.22 (s, 1H), 7.75 - 7.66 (m, 1H), 7.53 7.17 (m, 6H), 7.09 - 6.79 (m, 3H), 5.87 - 5.65 (m, 1H), 4.90 - 4.87 (m, 1H), 4.72 -4.68 (m, 1H),

4.42 - 4.39 (m, 1H), 2.89 - 2.76 (m, 1H), 2.67 - 2.55 (m, 1H), 2.39 - 2.33 (m, 6H), 2.20 - 2.09

(m, 1H), 1.82 - 1.80 (m, 1H).

[0337] Example 7: Preparation of compound 7

NBoc NH CI CI

I I O O

1-46 Compound 7

[0338] Intermediate 1-46 (40 mg, 0.069 mmol) was dissolved in a solution of trifluoroacetic

acid in dichloromethane (1/10, 3 mL) at 25°C. The reaction mixture was stirred at room

temperature for 1 hour and then poured into cold saturated sodium bicarbonate aqueous

solution (20 mL), and extracted with dichloromethane/methanol (10/1, 20 mL x 2). The

organic phases were combined, washed with water (20 mL), and concentrated under reduced

pressure. The residue was purified by preparative HPLC (ammonium bicarbonate system) to

obtain compound 7.

[0339] LC-MS (ESI) [M-H]- 477.80.

[0340] 'H NMR (400 MHz, DMSO-d) 6 10.67 - 10.35 (m, 1H), 7.74 - 7.24 (m, 7H), 7.22

6.95 (m, 2H), 6.82 - 6.76 (m, 1H), 4.95 - 4.50 (m, 2H), 3.47 (m, 1H), 3.18 (t, J= 6.3 Hz,1H),

2.99 - 2.70 (m, 1H), 2.42 - 2.30 (m, 3H), 2.04 - 1.54 (m, 2H), 1.15 (t, J= 7.0 Hz, 1H), 1.04

0.95 (m, 1H).

[0341] Example 8: Preparation of compound 8

/INFmoc NH CI CI

N F3C N F 3C O O

1-48A (trans) Compound 8 (trans)

[0342] Intermediate I-48A (14 mg, 0.019 mmol) was dissolved in N,N-dimethylformamide (3 mL) at 25°C, and the mixture was added with pyrrolidine (35.50 mg, 0.50 mmol), and stirred

at 25°C for 1 hour. The reaction mixture was added ethyl acetate (20 mL) to dilute, washed

with water (10 mL x 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was

concentrated under reduced pressure and purified by C18 reverse phase chromatography

(formic acid system) to obtain compound 8.

[0343] LC-MS (ESI) [M+H]* 515.2.

[0344] 'H NMR (400 MHz, DMSO-d) 611.18 (s, 1H), 8.13 - 7.90 (m, 2H), 7.88 - 7.52 (m, 6H), 7.09 (dd, J= 8.3, 2.7 Hz, 1H), 6.89 (d, J= 8.3 Hz, 1H), 4.90 (dt, J= 13.7, 3.3 Hz, 1H),

4.14 (d, J= 9.2 Hz, 1H), 3.80 - 3.35 (m, 1 H), 3.15 - 3.03 (m, 1H), 3.03 - 2.92 (m, 1H), 2.66

(t, J= 12.7 Hz, 1H), 2.09 (dd, J= 12.1, 4.1 Hz, 2H), 1.86 - 1.64 (m, 2H), 1.64 - 1.51 (m, 1H).

[0345] Example 9: Preparation of compound 9 7INFmoc /-NH C' CI

N 0 F3C N C F3 C

0 \/N \~ N H /N H /

/ I-48B (cis) Compound 9 (cis)

[0346] Intermediate I-48B (4.00 mg, 0.0054 mmol) was dissolved in N,N dimethylformamide (3 mL) at 25°C, and the mixture was added with pyrrolidine (35.50 mg,

0.50 mmol), and stirred at 25°C for 1 hour. The reaction mixture was added ethyl acetate (20

mL) to dilute, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, and filtered.

The filtrate was concentrated under reduced pressure and purified by C18 reverse phase

chromatography (formic acid system) to obtain compound 9.

[0347] LC-MS (ESI) [M+H]* 515.2.

[0348] 'H NMR (400 MHz, DMSO-d) 611.19 (s, 1H), 8.13 - 7.90 (m, 2H), 7.86 - 7.58 (m,

6H), 7.12 (dd, J= 8.2, 2.6 Hz, 1H), 6.93 - 6.74 (m, 1H), 4.70 (d, J= 9.4 Hz, 1H), 3.99 (td, J=

13.4, 3.5 Hz, 1H), 3.37 (m, 1H), 3.11 - 2.90 (m, 2H), 2.47 - 2.28 (m, 1H), 2.06 - 1.85 (m, 2H),

1.20 - 0.78 (m, 3H).

[0349] Example 10: Preparation of compound 1OA and compound 10B

NH NH NH CI CI CI SFC Separation N F3C N oF3 C N F3 C

Compound 8 (trans) Compound 10A Compound 10B

[0350] Compound 8 was resolved by SFC to obtain compound 10A (Rt = 1.424 min) and compound 1OB (Rt = 1.993 min).

[0351] Chiral resolution method:

[0352] Instrument: MG II preparative SFC(SFC-14)

[0353] Chromatographic column: ChiralPak AD, 250x30mm I.D.,10pm

[0354] Mobile phase: A: carbon dioxide B: ethanol (0.1% ammonia water)

[0355] Elution gradient: 35% B

[0356] Flow rate: 80 mL/min

[0357] Back pressure: 100 bar

[0358] Column temperature: 38°C

[0359] Detection wavelength: 220 nm

[0360] Cycle time: about 8 minutes

[0361] Chiral analysis method:

[0362] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0363] Chromatographic column: ChiralPak AD, 150x4.6mm I.D., 3pm

[0364] Mobile phase: A: carbon dioxide B: ethanol (0.05% diethylamine)

[0365] Elution gradient: 40% B

[0366] Flow rate: 2.5 mL/min

[0367] Back pressure: 1500 psi

[0368] Column temperature: 35°C

[0369] Detection wavelength: 220 nm

[0370] Compound 1OA:

[0371] Rt = 1.424 min

[0372] LC-MS (ESI) [M+H]* 515.2.

[03731 'H NMR (400 MHz, DMSO-d) 611.18 (s, 1H), 8.30 - 7.88 (m, 2H), 7.88 - 7.55 (m,

6H), 7.10 (dd,J= 8.4, 2.7 Hz, 1H), 6.89 (d,J= 8.3 Hz, 1H), 4.90 (dt,J= 13.5,3.2 Hz, 1H),

4.14 (d, J= 9.2 Hz, 1H), 3.40 - 3.39 (m, 1 H), 3.13 - 2.90 (m, 2H), 2.66 (t, J= 12.3 Hz, 1H),

2.16 - 2.05 (m, 2H), 1.87 - 1.49 (m, 3H).

[0374] Compound 1OB:

[0375] Rt = 1.993 min

[0376] LC-MS (ESI) [M+H]* 515.0.

[03771 'H NMR (400 MHz, DMSO-d) 611.18 (s, 1H), 8.12 - 7.89 (m, 2H), 7.87 - 7.59 (m, 6H), 7.18 - 7.03 (m, 1H), 6.90 (d, J= 8.4 Hz, 1H), 4.98 - 4.83 (m, 1H), 4.17 (m, 1H), 3.11

2.92 (m, 2H), 2.73 - 2.60 (m, 1H), 2.15 - 2.02 (m, 2H), 1.86 - 1.66 (m, 2H), 1.64 - 1.52 (m,

1H).

[0378] Example 11: Preparation of compound 11 Boc H N N H H H- CI H- CI

N 0 F3C N F3C

'/ N 0 H O 1-60 Compound 11

[0379] Intermediate 1-60 (15.0 mg, 0.0244 mmol) was dissolved in dichloromethane (0.5 mL)

at room temperature, and trifluoroacetic acid (0.5 mL) was added dropwise thereto while

stirring at room temperature, and the reaction mixture was stirred at room temperature for 2

hours. The mixture was concentrated and purified by preparative HPLC (ammonia water

system) to obtain compound 11.

[0380] LC-MS (ESI) [M+H]* 515.2.

[0381] 'HNMR(400 MHz, DMSO-d) 611.17 (s, 1H), 8.10-7.94 (m, 2H), 7.81 (d,J= 7.6

Hz,1H),7.78- 7.58(m,4H),7.23(d,J=2.4Hz,1H),7.12(dd,J= 8.6,2.4Hz,1H),6.94(d,

J= 8.3 Hz, 1H), 4.90 (d, J= 13.9 Hz, 1H), 3.77 - 3.64 (m, 1H), 3.59 - 3.50 (m, 1H), 3.21

3.07 (m, 3H), 2.74 - 2.61 (m, 2H), 2.10 - 2.01 (m, 1H), 1.84 - 1.66 (m, 2H).

[0382] Experimental example 1: IC5 0 test of inhibition of compounds on vasopressin

induced activation of vasopressin receptor V2R

[0383] (1) Cell

[0384] HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-V2R): The cell line was constructed by Shanghai Genechem Co., Ltd. using a lentivirus infection method,

and verified via qPCR that human V2R was stably expressed.

[0385] (2) Reagent

[0386] DMEM cell medium: Brand: Gibco, Item No.: 11995065; Fetal Bovine Serum: Brand: Genetimes, Item No.: FND500; 0.25% Trypsin: Brand: Gibco, Item No.: 25200072; Puromycin

Dihydrochloride: Brand: Gibco, Item No.: A1113803; cAMP-GS HIRANGE KIT: Brand:

Cisbio, Item No.: 62AM6PEC; IBMX: Brand: Sigma, Item No.: i5879; vasopressin AVP:

customized by GL Biochem (Shanghai), Ltd.

[0387] (3) Test method

[0388] HeLa-V2R cells were incubated with DMEM medium supplemented with 10% fetal bovine serum under the condition of 37°C and 5% C02, and the medium was added with 2

pg/mL puromycin to continuously screen cells expressing V2R. On the day of the experiment,

the cells were digested with trypsin, washed twice with the stimulation buffer in the cAMP-GS

HIRANGE kit, resuspended, and counted to prepare 1.6 x 106 cells/mL, and IBMX was added

until a final concentration of 0.5 mM. 5 L of cell suspension/well was transferred to a 384

well plate. To the corresponding wells were added 2.5 L of various concentrations of the

test compounds (3-fold dilution from 10 M, 10 concentration gradients) or DMSO (minimum

value Min, maximum value Max as a control), respectively. After incubating at room

temperature for 30 minutes, the test compound well and the maximum value well were added

with 2.5 L of vasopressin AVP solution until a final concentration of 2.25 nM, and the

minimum value well was added with 2.5 L of the stimulation buffer, and the plate was

incubated at 25°C for 60 minutes. At the same time, cAMP standard samples (3-fold dilution

from 5.6 M, 10 concentration points) were prepared, and 10 L of cAMP standard samples

were transferred to corresponding wells of a 384-well plate. The cAMP-d2 fluorescence and

anti-cAMP antibody probes provided in the kit were 20-fold diluted by the lysis buffer in the

cAMP-GS HIRANGE kit. To each well of a 384-well plate was sequentially added 5 L of

each diluted reagent. The above mixture in each well was mixed well, centrifuged briefly,

incubated at 25°C for 2 hours, and tested. The sample was tested by the HTRF method with the Envision microplate reader to determine the fluorescence intensity at 615 nm and 665 nm.

Each test sample was tested in duplicate, with 32 replicates for both Min and Max, respectively.

[0389] (4) Data processing

[0390] The fluorescence intensity ratio F1 6 6 5/ 6 15 at the wavelength of 665 nm and 615 nm of

the samples in each well was calculated. The logarithm of the concentration of the standard

was taken as X, and F16 6 5/ 6 1 5 x1000 as the Y value, and the standard curve was obtained by

fitting the "log(inhibitor) vs response - variable slope (four parameters)" model in Prism 8.0

software. F1665/615 x 1000 of the test well was taken as the Y value, and the cAMP

concentration corresponding to each sample was calculated in the Prism 8.0 software according

to the above standard curve.

[0391] %Inhibition (inhibition percentage) calculation formula is as follows:

[0392] % inhibition = (Cmax - Ccmpd)/(Cmax - Cmin) x 100

[0393] wherein Cmax is the average calculated value of cAMP concentration in all

maximum wells; Cmin is the average calculated value of cAMP concentration in all

minimum wells; Ccmpd is the calculated value of cAMP concentration of the test compound.

[0394] %Inhibition (inhibition percentage) was taken as the Y value, and the logarithmic

value of the compound concentration was taken as the X value, and the ICso was calculated by

nonlinear regression with "log(inhibitor) vs response - variable slope (four parameters)" model

in Prism 8.0 software, wherein Y = Bottom + (Top - Bottom)/(1 + 10^((LogICso - X) x Hill

Slope)).

[0395] The experimental results are shown in Table 1:

[0396] Table 1: Evaluation of compounds on inhibition of cAMP increase in human cervical

cancer cells (Human V2R Hela-Stable cell line OE2)

Compound number ICso (nM) Compound number ICso (nM)

1 14.65 2 32.62

3A 84.73 4 7.45

5 61.55 6 3.85

7 92.68 8 69.52 10A 30.97

[0397] Experimental example 2: In vivo pharmacokinetic experiment of compounds of the present disclosure

[0398] In this experimental example, in vivo pharmacokinetic evaluations were performed on mice by intravenous injection and oral administration.

[0399] Experimental methods and conditions: Male CD1mice, 6 to 8 weeks old with free access to food and water, were administered by oral gavage with a dosage of 10 mg/kg (solvent

5% DMSO/10% Solutol/85% Saline). 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8

hours, 10 hours, 24 hours after administration, blood samples were collected. Each sample

was collected in a volume of 150 L and anticoagulated with heparin sodium, placed on ice

after collection, and centrifuged within 1 hour to separate the test plasma. The plasma

concentration in plasma was tested by liquid chromatography-tandem mass spectrometry

(LC/MS/MS), and pharmacokinetic parameters were calculated using Phoenix WinNonlin

software via the measured concentration. Tolvaptan was taken as the reference substance 1,

and the experimental results are shown in Table 2.

[0400] Table 2: Pharmacokinetics of oral administration (10 mg/kg)

Compound T1/2 (hr) Cmax (ng/mL) AUCo-inf (ng * hr/mL) F (%)

Compound 10A 4.44 833.03 2026.32 73.34

Reference 1.58 1307 1613 44

substance 1

[0401] Experimental data indicate that the in vivo pharmacokinetics results of oral

administration of the compounds of the present disclosure to mice show longer half-life T/2

and higher exposure AUCo-inf in vivo.

[0402] Experimental example 3: Test of inhibitory effect of compounds on LLC-PK1 cell

proliferation

[0403] (1) Cells

[0404] Porcine renal epithelial cell LLC-PK1: purchased from ATCC, Cat#CL-101

[0405] (2) Reagents:

[0406] Medium 199, Gibco (Cat#11150059)

[0407] Fetal Bovine Serum (FBS), Australia, Genetimes (Cat# FND500)

[0408] Trypsin-EDTA (0.25%), phenol red, Gibco (Cat# 25200072)

[0409] PBS, pH 7.4, Gibco (Cat# 10010031)

[0410] DMSO (dimethyl sulfoxide), Sigma (Cat# D8418)

[0411] Poly-D-lysine, Gibco (Cat# A3890401)

[0412] Vasopressin AVP: Customized by GL Biochem (Shanghai), Ltd.

[0413] Verapamil hydrochloride, MCE (Cat# HY-A0064)

[0414] AlamarBlue T MHS Cell Viability Reagent, Invitrogen (Cat# A50100)

[0415] (3) Test method:

[0416] The pathogenesis of polycystic kidney disease is related to the low intracellular calcium ion concentration of renal collecting duct epithelial cells and the cAMP-dependent

excessive proliferation of cells. Referring to the research paper published by Tamio

Yamaguchi et al. in The JournalofBiological Chemistry in 2004, we optimized and carried

out the LLC-PK1 proliferation assay of renal epithelial cells to evaluate the inhibiting effects

of compounds on vasopressin-induced cell proliferation after reducing the intracellular calcium

ion concentration.

[0417] LLC-PK1 cells were incubated with M199 medium supplemented with 10% fetal

bovine serum under the condition of 37°C and 5% CO 2 . On the first day of the experiment, a

96-well plate was coated with 0.01% Poly-D-lysine, then each well of the plate was added with

100 L of the above mixture. After standing at room temperature for 10 minutes, the mixture

in each well was aspirated and air-dried at room temperature for 1 hour, and washed once with

200 L 1 x PBS for further use. LLC-PK1 cells were digested with trypsin, resuspended with

serum-free M199 after centrifugation, counted, diluted into 1 x 10 5/mL cell suspension with

serum-free M199 medium, and added with FBS until 1% final concentration. To a 96-well

plate was transfered 200 L of cell suspension/well. After the cells were incubated for 24

hours, the supernatant of the formulated solution was aspirated, and the cells were washed once

with200[LofPBS. Then 160 L of M199 medium containing 0.05% FBS and 20 L of 10

x Verapamil (final concentration of 5 M) were sequentially added thereto, and the culture was

continued for 24 hours. To the corresponding wells was respectively added 10 L of various

concentrations of the test compound (final concentration starting from 3 M, 3-fold dilution, 8 concentration gradients) or DMSO (Min, and Max as a control) on the third day. To the test compound well and the maximum value well was added 10 L of vasopressin AVP solution until a final concentration of 10 nM, and to the minimum value well was added 10 L of serum free M199 medium, and each well was continued to incubate for 48 hours. Onthefifthday, the culture medium was carefully aspirated. The cells were washed once with 200 L of PBS.

90 L of M199 serum-free medium was carefully added thereto, and then 10 L of Alamarblue

reagent was added thereto. The mixture was centrifuged at 300 rpm for 1 minute, incubated

at 37°C for 2 hours, and then tested. SpectraMax instrument was used for the sample test.

The excitation light was 560 nm, and the emission light was 595 nm. Each test sample was

tested in triplicate, with 6 replicates for both Min and Max, respectively.

[0418] (4) Data processing

[0419] The concentration of the compound was taken as the X value, and the average value of the fluorescence intensity of each experimental well sample minus the fluorescence intensity

of the background well was taken as the Y value, which represented the number of living cells

in the well at the time of testing. The Grouped-Summary data-Separated bar graph in

GraphPad Prism 8.0 software was used to make a bar chart for reflecting the dose-effect

relationship of different compounds on AVP-induced cell proliferation. Tolvaptan was used

as a positive control for qualitatively evaluating the inhibitory effect of the compounds on

proliferation: compounds whose overall performance was better than that of Tolvaptan were

represented as "+++", those whose performance was close to Tolvaptan were represented as

"++", those whose performance was weaker than Tolvaptan were represented as "+", and those

with no proliferation inhibition were represented as "-".

[0420] Data quality control: S/B was calculated, i.e., the average value of the Max well/the

average value of the Min well > 2 was regarded as a QC pass.

[0421] The experimental results indicate (see Figure 1, Figure 2, and Table 3 below) that in

the AVP-induced LLC-PK1 cell proliferation assay, Tolvaptan, as a positive reference,

exhibited a high-concentration pro-proliferative hook effect, while compound 1 had no hook

effect, showing a dose-response superior to that of Tolvaptan.

[0422] Table 3: Inhibitory effect of compounds on LLC-PK1 cell proliferation

Proliferation inhibition grading

Compound Repeated Repeated

experiment I experiment II

Reference substance 1 ++ ++

Compound 10A +++ +++

[0423] Experimental example 4: Binding test of compounds to Vla, Vib, V2 receptors

[0424] In this experiment, the affinity Ki of compound 1 and reference substance 1 to human

VIaR, V1bR, and V2R was tested by a competitive isotope ligand binding experiment.

[0425] (1) Cell membrane

[0426] The cells with high expression of human Vla receptor were amplified, collected, washed twice with PBS, resuspended with PBS containing a protease inhibitor, homogenized

with a homogenizer at 15000 r/min to break the cells, and centrifuged at 4°C and 3000 r/min

for 15 minutes. The supernatant was collected, centrifuged at 20,000 r/min at 4°C for 45

minutes. Then the supernatant was discarded to obtain a cell membrane precipitation.

Buffer was added to resuspend to measure the protein concentration, aliquoted, and stored at

80°C. The cell membranes of highly expressed human Vib and V2 receptors were purchased

from Perkinelmer, USA.

[0427] (2) Assay buffer

[0428] 50 mM Tris-HCl, pH 7.4

[0429] 10 mM MgCl2

[0430] 0.1% BSA

[0431] Protease inhibitor mixture (one tablet/50 mL)

[0432] (3) Wash buffer

[0433] 50 mM Tris-HCl, pH 7.4

[0434] (4) Compound preparation

[0435] 1. Preparation of a stock solution of compounds

1.59 mg, 1.24 mg, and 1.38 mg of the test compound were taken, respectively, and dissolved

in 100% dimethyl sulfoxide until a final concentration of 10 mM. Positive control vasopressin was prepared as a 10 mM stock solution.

[0436] 2. Preparation of 100 x compounds

[0437] The stock solution of the test compound and that of the positive control were diluted

to 1 mM (10-fold dilution) and 0.1 mM (100-fold dilution) with DMSO, respectively, and then

sequentially subjected to a four-fold dilution with DMSO to the tenth point.

[0438] 3. Preparation of cell membrane stock solution

[0439] Cell membranes overexpressing human receptors were prepared with assay buffer to

5 mg/mL.

[0440] (5) Operating steps

[0441] 1. 1 L of the compound was aspirated from the dilution plate into each well of the

96-well assay plate (the concentration of the test compound in the reaction would be diluted

100-fold). To the control well was added 1 L of DMSO.

[0442] 2. 10 mL of membrane solution containing 5 g/tL was prepared.

[0443] 3. To the compound assay plate was added the membrane solution from step 2 with a

pipette, and each well was added with 89 L of the membrane solution.

[0444] 4. The 50 Ci/mL isotope-labeled vasopressin stock solution was diluted with assay

buffer to a 10-fold final concentration, and the reaction plate was added with 10 L/well with

a pipette. The final concentrations of the isotope-labeled vasopressin in Vla, VIb, and V2

receptor experiments were 1.5 nM, 0.75 nM, and 1 nM, respectively.

[0445] 5. The configured test plate was placed at 30°C and incubated for 60 minutes.

[0446] 6. The membrane complexes were collected into 0.5% PEI pre-coated GF/B plate with

Cell Harvester, washed 3 times with 2 mL of pre-cooled elution buffer at 4°C, and dried at

37°C for 2 hours.

[0447] 7. The content of isotope-labeled vasopressin bound to the receptor was measured with

a liquid scintillation/luminescence counter.

[0448] 8. The read data was processed with prism 5, and the dose-effect curve of the

compound and the IC50 value of the compound competitively inhibiting the binding of isotope

labeled vasopressin to the receptor were obtained by fitting with the following equation.

[0449] Y = Bottom + (Top - Bottom)/(1 + 10^((X - LogIC50))), wherein: Y is the reading

value of the liquid scintillation counter, and X is the logarithmic value of the compound concentration. The affinity of the compound for the receptor, Ki, was calculated from the

IC50 value using the following equation: Ki = IC50/(1 + ([L]/Kd)), wherein [L] is the

concentration of isotope-labeled vasopressin in the test, and Kd is the dissociation constant

between isotope-labeled vasopressin and the receptor.

[0450] The results of the two repeated experiments are shown in Table 4. The binding Ki of vasopressin to the three receptors was close to that reported in the literature, and neither

compound 1A nor reference substance 1 bound to the Vib receptor (IC50 >10 M); the

binding affinity of compound 1OA and reference substance 1 for V2R was higher than that for

VIa, with varying degrees of Vla/V2 selectivity.

[0451] Table 4: Binding affinity of test compounds to Vla, Vlb, V2 receptors

(nM) VlaR V1bR V2R

Compound N=1 N=2 N=1 N=2 N=1 N=2

19.71 11.14 >10 M >10 M 2.1 2.76 Compound 10A 15.4±4.3 >10 M 2.4±0.3

Reference 23.32 20.4 >10 M >10 M 0.27 0.6

substance 1 21.9±1.5 >10 M 0.44±0.17

0.37 0.27 0.15 0.27 0.75 1.2 Vasopressin 0.32±0.05 0.21±0.06 0.98±0.23

Claims

What is claimed is: 1. A compound of formula (I), an optical isomer thereof, or a pharmaceutically acceptable

salt thereof,

A

2P RI

N Ti O

O N H (1)

wherein ring A is selected from 4- to 5-membered heterocyclyl, and the 4- to 5-membered heterocyclyl is optionally substituted by 1, 2, or 3 RA;

ring B is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R3 ; ring C is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4 ; TI, T2are each independently selected from N andC(RT); RI, R2, R3, RA, RTare each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1.

6alkyl, andC 1 -6heteroalkyl, and theCI-6alkyl orC1 -6heteroalkyl is optionally substituted by 1, 2, or 3 R; each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C 1- 6

alkoxy,C 1-6alkylamino,C 3-6cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the Ci

6alkyl, C1-6alkoxy,C 1 -6alkylamino,C 3-6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4a; R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6alkyl, C1

6 alkoxy, andC1-6 alkylamino, and the C 1-6 alkyl, C1 -6 alkoxy, andC-6 alkylamino are optionally substituted by 1, 2, or 3 R'; R' is selected from H, F, Cl, Br,I, CN, OH, NH 2 , andC1 -6alkyl; ml, m2 are each independently selected from 0, 1, or 2; the 4- to 5-membered heterocyclyl comprises only 1 heteroatom or heteroatom group, and the heteroatom or heteroatom group is selected from -0-, -NH-, and N; the C1-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=0)-, -C(=0)O-, -S(=0)-,

-S(=0) 2 -, and N.
2. A compound of formula (III), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,

R2 r 22 R1

N T1 R3

) 0II 0 Y2 Y1 N ,

H

wherein one of X1, X2 and X3 is selected from 0 and NRA, and the others are C(RA)2; Ti, T2 are each independently selected from N and C(RT); Y 1, Y2 are each independently selected from N and C(Ry);

Ri, R2 , R3 , RA, RT, Ry are each independently selected from H, F, Cl, Br, I, CN, OH, NH2

, C 1-6 alkyl, and C 1-6 heteroalkyl, and the C1-6 alkyl or C1 -6 heteroalkyl is optionally substituted

by 1, 2, or 3 R; each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C1-6 alkoxy, C 1-6alkylamino, C 3 -6cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the C1 .

6 alkyl, CI-6 alkoxy, C1-6 alkylamino, C 3 -6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R4a; R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, Ci

6 alkoxy, and Ci-6 alkylamino, and the C1 -6 alkyl, C1 -6 alkoxy, and C1-6 alkylamino are

optionally substituted by 1, 2, or 3 R'; R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , and C1 -6alkyl; ml, m2, m3, m4 are each independently selected from 0, 1, or 2; n is 0 or 1; the CI-6 heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S-, -C(=0)-, -C(=0)O-, -S(=0)-,

-S(=0) 2-, and N.
3. A compound of formula (IV), an optical isomer thereof, or a pharmaceutically

acceptable salt thereof, RA N

R2 M2R, mT2

N T, R3)M 3

o R4 Y2 , "' H (IV)

wherein T1, T2 are each independently selected from 0, N, andC(RT);

Yi, Y2 are each independently selected from N and C(Ry);

Ri, R2 , R3 , RA, RT, Ry are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2

, C 1-6 alkyl, and C 1-6 heteroalkyl, and the C1-6 alkyl or C 1-6 heteroalkyl is optionally substituted

by 1, 2, or 3 R;

each R4 is independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C1-6

alkoxy, C1-6 alkylamino, C 3 -6 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, and the C1

6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C 3 -6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl

is optionally substituted by 1, 2, or 3 R4a;

R, R4 a are each independently selected from H, F, Cl, Br, I, CN, OH, NH 2 , C1-6 alkyl, C1 .

6 alkoxy, and C1-6 alkylamino, and the C 1 .6 alkyl, C1-6 alkoxy, and C1-6 alkylamino are

optionally substituted by 1, 2, or 3 R';

R'is selected from H, F, Cl, Br, I, CN, OH, NH 2 , and C 1 -6 alkyl;

m2, m3 are each independently selected from 0, 1, or 2;

n is 0 or 1;

the C 1 -6heteroalkyl or 5- to 6-membered heteroaryl comprises 1, 2, 3, or 4 heteroatoms or

heteroatom groups independently selected from -0-, -NH-, -S-, -C(=)-, -C(=O)O-, -S(=O)-,

-S(=0) 2 -, and N.
4. A compound of formula (V-1), (V-2), (V-3), or (V-4), an optical isomer thereof, or a

pharmaceutically acceptable salt thereof,

NRA R R1 (R RA

(R m2

T1; RT N T 1;,--T N I RR N R4 RL R

YN 1 H Y N H

(V-i) (V-2)

N

N TT R3 )a N T, R 3)ta (v-3 m2,(v4

HJ Y1 N N H H (V-3) (V-4)

wherein TI,T 2 , Y1,Y2 , RI,R2 , R3 , R 4 , RA, m2, m3, nare as defined in claim 3.
5. The compound, the optical isomer thereof, orthe pharmaceutically acceptable salt

thereof according to any one of claims 1 to 4, wherein R4 is selected from H, F, Cl, Br, I, CN,

OH, NH2 , CH3 , CF 3 ,"', 0 ' , I , cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thienyl, and thiazolyl.
6. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt

thereof according to claim 1, wherein ring A is selected from azetidinyl, oxetanyl, pyrrolidinyl,

and tetrahydrofuranyl, and the azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl is

optionally substituted by 1 or 2 RA.
7. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt

qNH qN- QO

thereof according to claim 6, wherein ring A is selected from H N NH

, ' ', and ''
8. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is selected from phenyl and pyridyl, and the phenyl or pyridyl is optionally substituted by 1, 2, or 3 R 3

.
9. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt

thereof according to claim 8, wherein ring B is selected from and N
10. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt

Cl F

thereof according to claim 1, wherein ring C is selected from ,and
11. A compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

NHNH N-0 C ci CF 1 \CI

N&0 0 bN N N \N N N H0

H N 0 NH CI C CI F

N N i N

HH H
12. The compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to claim 11, wherein the optical isomer is selected from: N /NH c F CI CI

Na F3 C N 0 F3 N 0 F

\N H / , N1H N H

NH NH NH CI CI C1

N F 3C N F3 C N F 3C

No Nand H N H Hill CI

N

H
13. A use of the compound, the optical isomer thereof, or the pharmaceutically acceptable

salt thereof according to any one of claims 1 to 12 in the manufacture of a medicament for the

prevention or treatment of diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vib receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system.
14. The use according to claim 13, wherein the diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vib receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system comprise: hypertension, Reye's syndrome, dysmenorrhea, premature delivery, corticotropin-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone secretion, hyponatremia caused by chronic heart failure/liver cirrhosis/inappropriate antidiuretic hormone secretion, or polycystic kidney disease.
15. A method for the prevention or treatment of diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vib receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system, said method comprising administering to a patient in need a compound, the optical isomer thereof, or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 12.
16. The method of claim 15 wherein the diseases related to arginine vasopressin Vla receptor, arginine vasopressin Vib receptor, arginine vasopressin V2 receptor, sympathetic nervous system, or renin-angiotensin-aldosterone system comprise: hypertension, Reye's syndrome, dysmenorrhea, premature delivery, corticotropin-releasing hormone secretion disorder, adrenal hyperplasia, depression, chronic congestive heart failure, liver cirrhosis, syndrome of inappropriate antidiuretic hormone secretion, hyponatremia caused by chronic heart failure/liver cirrhosis/inappropriate antidiuretic hormone secretion, or polycystic kidney disease.